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Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025; 17:103839. [PMID: 40177195 PMCID: PMC11959660 DOI: 10.4254/wjh.v17.i3.103839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
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Affiliation(s)
- Li-Li Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Man-Lu Guo
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Hua Wu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China.
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Tagami G, Yamaguchi M, Sugiyama H, Kinashi H, Imai K, Kamiya K, Katsuno T, Imaizumi T, Banno S, Ito Y, Ishimoto T. Efficacy and safety of avacopan in antineutrophil cytoplasmic autoantibody-associated vasculitis: a retrospective cohort study in Japan. BMC Rheumatol 2025; 9:8. [PMID: 39844309 PMCID: PMC11756139 DOI: 10.1186/s41927-025-00456-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Avacopan, an oral C5a receptor antagonist, demonstrated efficacy as an alternative to glucocorticoid therapy in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in the phase 3 ADVOCATE trial. However, limited real-world data exist on the outcomes and experiences associated with avacopan use for AAV in Japan. METHODS We performed a single-centre retrospective analysis and evaluated 21 patients with newly diagnosed or relapsed AAV who received avacopan. The co-primary outcomes were clinical remission at 6 and 12 months. RESULTS Among the 21 patients, 20 (95.2%) achieved clinical remission at 6 months, and 19 (90.4%) sustained remission at 12 months. The median time from initiation of immunosuppressive therapy to the start of avacopan was 12 days (interquartile range, 5-26). Adverse events were reported in 10 patients (47.6%), with elevated liver enzyme levels observed in eight patients (38.1%) as the most frequent complication. Avacopan was discontinued in nine patients (42.9%). Despite early discontinuation, these patients achieved comparable rates of clinical remission at 6 months, sustained remission at 12 months, and experienced a reduction in glucocorticoid doses relative to those who continued avacopan. CONCLUSIONS A high incidence of adverse events, particularly liver enzyme elevation, and frequent early discontinuations of avacopan were observed. Nevertheless, favourable clinical outcomes and reduced glucocorticoid doses were achieved regardless of avacopan discontinuation. Further studies are warranted to validate the optimal use of avacopan in clinical practice.
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Affiliation(s)
- Genri Tagami
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Makoto Yamaguchi
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Hirokazu Sugiyama
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Hiroshi Kinashi
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Kentaro Imai
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Keisuke Kamiya
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
- Department of Nephrology and Rheumatology, Aichi Medical University Medical Center, Okazaki, Aichi, Japan
| | - Takahiro Imaizumi
- Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Shogo Banno
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Yasuhiko Ito
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
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Emine Rabia K, Ömer Faruk T, Furkan S, Lazrak ES, Ozen PA, Tuncer A. Probable eculizumab-associated hepatotoxicity in a patient with neuromyelitis optica: a case report. Int J Neurosci 2024; 134:1205-1209. [PMID: 37632449 DOI: 10.1080/00207454.2023.2253361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 07/06/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
OBJECTIVES Neuromyelitis optica (NMO) is an inflammatory, autoimmune and demyelinating disease of the central nervous system and is often characterized by attacks of severe optic neuritis and long segment myelitis. Identifying the disease-specific pathogenic anti-AQP4 autoantibody in NMOSD has allowed the development of highly effective disease-modifying drugs in the treatment phase. Eculizumab is a humanized antibody that binds to complement C5 and inhibits the formation of the C5b-induced membrane attack complex. It is approved for treating many diseases in which tissue damage is accompanied by complement (such as neuromyelitis optica, myasthenia gravis, autoimmune hemolytic anemia and paroxysmal hemoglobinuria). METHODS We present a patient diagnosed with NMO who developed possible drug-induced liver injury three months after the start of eculizumab treatment. RESULT After discontinuing eculizumab treatment, liver function tests gradually regressed in a month. CONCLUSIONS Eculizumab-associated hepatotoxicity is a previously unreported adverse event in NMOSD patients. Therefore, patients should be monitored for liver function tests during eculizumab treatment, and care should be taken for hepatotoxicity. If hepatotoxicity is detected while under eculizumab treatment, patients should be investigated for other drug use, complementary food supplementation, or possible autoimmune hepatitis, and other potential causes should be excluded.
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Affiliation(s)
- Koc Emine Rabia
- Department of Neurology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Turan Ömer Faruk
- Department of Neurology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Saridas Furkan
- Department of Neurology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | | | - Pinar Acar Ozen
- Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Aslı Tuncer
- Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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Li CM, Sun T, Yang MJ, Yang Z, Li Q, Shi JL, Zhang C, Jin JF. Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice. World J Hepatol 2024; 16:1188-1198. [PMID: 39474574 PMCID: PMC11514617 DOI: 10.4254/wjh.v16.i10.1188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen (APAP). However, the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.
AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.
METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury. C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment. We detected the effects of C2-FH on liver function, inflammatory response and complement activation. Additionally, RNA-sequencing (RNA-Seq) analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.
RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity, aspartate aminotransferase activity and lactate dehydrogenase, and reduced liver tissue necrosis caused by APAP. Moreover, it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury. RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.
CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.
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Affiliation(s)
- Chun-Mei Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Tian Sun
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Mou-Jie Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Zhi Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Qing Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jia-Lin Shi
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Chong Zhang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jun-Fei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
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Li CM, Sun T, Yang MJ, Yang Z, Li Q, Shi JL, Zhang C, Jin JF. Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice. World J Hepatol 2024; 16:1368-1378. [DOI: 10.4254/wjh.v16.i10.1368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen (APAP). However, the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.
AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.
METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury. C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment. We detected the effects of C2-FH on liver function, inflammatory response and complement activation. Additionally, RNA-sequencing (RNA-Seq) analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.
RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity, aspartate aminotransferase activity and lactate dehydrogenase, and reduced liver tissue necrosis caused by APAP. Moreover, it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury. RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.
CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.
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Affiliation(s)
- Chun-Mei Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Tian Sun
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Mou-Jie Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Zhi Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Qing Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jia-Lin Shi
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Chong Zhang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jun-Fei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
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Magdy A, Kim HJ, Go H, Lee JM, Sohn HA, Haam K, Jung HJ, Park JL, Yoo T, Kwon ES, Lee DH, Choi M, Kang KW, Kim W, Kim M, on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium. DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2024; 30:824-844. [PMID: 39048522 PMCID: PMC11540403 DOI: 10.3350/cmh.2024.0229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND/AIMS Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. METHODS Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. RESULTS Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. CONCLUSION Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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Affiliation(s)
- Amal Magdy
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hee-Jin Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hanyong Go
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Jun Min Lee
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hyun Ahm Sohn
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Keeok Haam
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hyo-Jung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Jong-Lyul Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Taekyeong Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Eun-Soo Kwon
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mirang Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Bouwman HB, Guchelaar HJ. The efficacy and safety of eculizumab in patients and the role of C5 polymorphisms. Drug Discov Today 2024; 29:104134. [PMID: 39111540 DOI: 10.1016/j.drudis.2024.104134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/11/2024] [Accepted: 07/31/2024] [Indexed: 08/13/2024]
Abstract
Eculizumab is an orphan drug with indications for extremely rare autoimmune disorders. It is primarily prescribed for use in patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome; but is also highly effective in the treatment of myasthenia gravis, among others. By binding to the C5 protein in the complement system, eculizumab effectively inhibits cellular hemolysis and autoimmune reactions. Despite this effective treatment, some patients reported no improvement in symptoms. Genetic sequencing revealed three distinct C5 mutations in the non-responders and these polymorphisms appeared to be most prevalent among Japanese, Korean and African populations. Here, we present an overview of the current and potential future applications of eculizumab, as well as the disadvantages of eculizumab treatment in patients with C5 polymorphisms.
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Affiliation(s)
| | - Henk-Jan Guchelaar
- Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
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Mannes M, Savukoski S, Ignatius A, Halbgebauer R, Huber-Lang M. Crepuscular rays - The bright side of complement after tissue injury. Eur J Immunol 2024; 54:e2350848. [PMID: 38794857 DOI: 10.1002/eji.202350848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024]
Abstract
Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host-protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement-targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.
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Affiliation(s)
- Marco Mannes
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Susa Savukoski
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute for Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
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9
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Yang Z, Li C, Wang Y, Dong W, Yang M, Jin J. A single-chain antibody construct with specificity of a natural IgM antibody reduces hepatic ischemia reperfusion injury in mice. J Cell Mol Med 2024; 28:e18291. [PMID: 38597412 PMCID: PMC11005456 DOI: 10.1111/jcmm.18291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 03/18/2024] [Accepted: 03/25/2024] [Indexed: 04/11/2024] Open
Abstract
Natural immunoglobulin M (IgM) antibodies have been shown to recognize post-ischemic neoepitopes following reperfusion of tissues and to activate complement. Specifically, IgM antibodies and complement have been shown to drive hepatic ischemia reperfusion injury (IRI). Herein, we investigate the therapeutic effect of C2 scFv (single-chain antibody construct with specificity of a natural IgM antibody) on hepatic IRI in C57BL/6 mice. Compared with PBS-treated mice, C2 scFv-treated mice displayed almost no necrotic areas, significant reduction in serum ALT, AST and LDH levels, and significantly reduced in the number of TUNEL positive cells. Moreover, C2 scFv-treated mice exhibited a notable reduction in inflammatory cells after hepatic IRI than PBS-treated mice. The serum IL-6, IL-1β, TNF-α and MPC-1 levels were also severely suppressed by C2 scFv. Interestingly, C2 scFv reconstituted hepatic inflammation and IRI in Rag1-/- mice. We found that C2 scFv promoted hepatic cell death and increased inflammatory cytokines and infiltration of inflammatory cells after hepatic IRI in Rag1-/- mice. In addition, IgM and complement 3d (C3d) were deposited in WT mice and in Rag1-/- mice reconstituted with C2 scFv, indicating that C2 scFv can affect IgM binding and complement activation and reconstitute hepatic IRI. C3d expression was significantly lower in C57BL/6 mice treated with C2 scFv compared to PBS, indicating that excessive exogenous C2 scFv inhibited complement activation. These data suggest that C2 scFv alleviates hepatic IRI by blocking complement activation, and treatment with C2 scFv may be a promising therapy for hepatic IRI.
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Affiliation(s)
- Zhi Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Chunmei Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yongqin Wang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Wei Dong
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Moujie Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Junfei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
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10
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Nguyen VD, Hughes TR, Zhou Y. From complement to complosome in non-alcoholic fatty liver disease: When location matters. Liver Int 2024; 44:316-329. [PMID: 38010880 DOI: 10.1111/liv.15796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/21/2023] [Accepted: 11/09/2023] [Indexed: 11/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing public health threat and becoming the leading cause of liver transplantation. Nevertheless, no approved specific treatment is currently available for NAFLD. The pathogenesis of NAFLD is multifaceted and not yet fully understood. Accumulating evidence suggests a significant role of the complement system in the development and progression of NAFLD. Here, we provide an overview of the complement system, incorporating the novel concept of complosome, and summarise the up-to-date evidence elucidating the association between complement dysregulation and the pathogenesis of NAFLD. In this process, the extracellular complement system is activated through various pathways, thereby directly contributing to, or working together with other immune cells in the disease development and progression. We also introduce the complosome and assess the evidence that implicates its potential influence in NAFLD through its direct impact on hepatocytes or non-parenchymal liver cells. Additionally, we expound upon how complement system and the complosome may exert their effects in relation with hepatic zonation in NAFLD. Furthermore, we discuss the potential therapeutic implications of targeting the complement system, extracellularly and intracellularly, for NAFLD treatment. Finally, we present future perspectives towards a better understanding of the complement system's contribution to NAFLD.
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Affiliation(s)
- Van-Dien Nguyen
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Timothy R Hughes
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - You Zhou
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
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11
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Irfan M, Marzban H, Chung S. C5L2 CRISPR KO enhances dental pulp stem cell-mediated dentinogenesis via TrkB under TNFα-induced inflammation. Front Cell Dev Biol 2024; 12:1338419. [PMID: 38318114 PMCID: PMC10839780 DOI: 10.3389/fcell.2024.1338419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Background and Objectives: Dental caries is one of the most common human pathological conditions resulting from the invasion of bacteria into the dentin. Current treatment options are limited. In many cases, endodontic therapy leads to permanent pulp tissue loss. Dentin-pulp complex regeneration involves dental pulp stem cells (DPSCs) that differentiate into odontoblast-like cells under an inflammatory context. However, limited information is available on how DPSC differentiation processes are affected under inflammatory environments. We identified the crucial role of complement C5a and its receptor C5aR in the inflammation-induced odontoblastic DPSC differentiation. Methodology: Here, we further investigated the role of a second and controversial C5a receptor, C5L2, in this process and explored the underlying mechanism. Human DPSCs were examined during 7-, 10-, and 14-day odontogenic differentiation treated with TNFα, C5L2 CRISPR, and tyrosine receptor kinase B (TrkB) antagonist [cyclotraxin-B (CTX-B)]. Results: Our data demonstrate that C5L2 CRISPR knockout (KO) enhances mineralization in TNFα-stimulated differentiating DPSCs. We further confirmed that C5L2 CRISPR KO significantly enhances dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) expression after 14-day odontoblastic DPSC differentiation, and treatment with CTX-B abolished the TNFα/C5L2 CRISPR KO-induced DSPP and DMP-1 increase, suggesting TrkB's critical role in this process. Conclusion and Key applications: Our data suggest a regulatory role of C5L2 and TrkB in the TNFα-induced odontogenic DPSC differentiation. This study may provide a useful tool to understand the mechanisms of the role of inflammation in dentinogenesis that is required for successful DPSC engineering strategies.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Hassan Marzban
- Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
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12
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Kusakabe J, Hata K, Tajima T, Miyauchi H, Zhao X, Kageyama S, Tsuruyama T, Hatano E. Properdin inhibition ameliorates hepatic ischemia/reperfusion injury without interfering with liver regeneration in mice. Front Immunol 2023; 14:1174243. [PMID: 37662914 PMCID: PMC10469474 DOI: 10.3389/fimmu.2023.1174243] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (P <0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (P =0.010) and ssDNA+ cells (P <0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (P <0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (P =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines (P =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both P <0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (P =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.
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Affiliation(s)
- Jiro Kusakabe
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tetsuya Tajima
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidetaka Miyauchi
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Xiangdong Zhao
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tatsuaki Tsuruyama
- Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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13
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Irfan M, Chung S. C5L2 modulates BDNF production in human dental pulp stem cells via p38α pathway. Sci Rep 2023; 13:74. [PMID: 36593314 PMCID: PMC9807628 DOI: 10.1038/s41598-022-27320-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023] Open
Abstract
Tissue injury affects nerve fibers and triggers an immune response, leading to inflammation. The complement system gets activated during inflammatory conditions and has been reported to be involved in the regeneration process. We have demonstrated that the C5a receptor (C5aR) has crucial roles in regeneration and healing processes including nerve sprouting and hard tissue formation. Another C5a-like 2 receptor (C5AR2; C5L2) has been cloned which is still considered controversial due to limited studies. We previously established that C5L2 regulates brain-derived neurotrophic factor (BDNF) secretion in pulp fibroblasts. However, there is no study available on human dental pulp stem cells (DPSCs), especially in the inflammatory context. Stem cell therapy is an emerging technique to treat and prevent several diseases. DPSCs are a great option to be considered due to their great ability to differentiate into a variety of cells and secrete nerve regeneration factors. Here, we demonstrated that C5L2 modulates BDNF secretion in DPSCs. Our results stated that C5L2 silencing through siRNA could increase BDNF production, which could accelerate the nerve regeneration process. Moreover, stimulation with lipopolysaccharide (LPS) enhanced BDNF production in C5L2 silenced DPSCs. Finally, we quantified BDNF secretion in supernatant and cell lysates using ELISA. Our results showed enhanced BDNF production in C5L2 silenced DPSCs and hampered by the p38MAPKα inhibitor. Taken together, our data reveal that C5L2 modulates BDNF production in DPSCs via the p38MAPKα pathway.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA.
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14
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Delaura IF, Gao Q, Anwar IJ, Abraham N, Kahan R, Hartwig MG, Barbas AS. Complement-targeting therapeutics for ischemia-reperfusion injury in transplantation and the potential for ex vivo delivery. Front Immunol 2022; 13:1000172. [PMID: 36341433 PMCID: PMC9626853 DOI: 10.3389/fimmu.2022.1000172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/05/2022] [Indexed: 01/21/2023] Open
Abstract
Organ shortages and an expanding waitlist have led to increased utilization of marginal organs. All donor organs are subject to varying degrees of IRI during the transplant process. Extended criteria organs, including those from older donors and organs donated after circulatory death are especially vulnerable to ischemia-reperfusion injury (IRI). Involvement of the complement cascade in mediating IRI has been studied extensively. Complement plays a vital role in the propagation of IRI and subsequent recruitment of the adaptive immune elements. Complement inhibition at various points of the pathway has been shown to mitigate IRI and minimize future immune-mediated injury in preclinical models. The recent introduction of ex vivo machine perfusion platforms provides an ideal window for therapeutic interventions. Here we review the role of complement in IRI by organ system and highlight potential therapeutic targets for intervention during ex vivo machine preservation of donor organs.
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Affiliation(s)
- Isabel F. Delaura
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Qimeng Gao
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Imran J. Anwar
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Nader Abraham
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Riley Kahan
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Matthew G. Hartwig
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, United States
| | - Andrew S. Barbas
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
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15
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Galili U, Goldufsky JW, Schaer GL. α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment. Int J Mol Sci 2022; 23:ijms231911490. [PMID: 36232789 PMCID: PMC9569695 DOI: 10.3390/ijms231911490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 09/27/2022] [Indexed: 12/02/2022] Open
Abstract
This review discusses a novel experimental approach for the regeneration of original tissue structure by recruitment of endogenous stem-cells to injured sites following administration of α-gal nanoparticles, which harness the natural anti-Gal antibody. Anti-Gal is produced in large amounts in all humans, and it binds the multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) presented on α-gal nanoparticles. In situ binding of anti-Gal to α-gal nanoparticles activates the complement system and generates complement cleavage chemotactic-peptides that rapidly recruit macrophages. Macrophages reaching anti-Gal coated α-gal nanoparticles bind them via Fc/Fc receptor interaction and polarize into M2 pro-reparative macrophages. These macrophages secrete various cytokines that orchestrate regeneration of the injured tissue, including VEGF inducing neo-vascularization and cytokines directing homing of stem-cells to injury sites. Homing of stem-cells is also directed by interaction of complement cleavage peptides with their corresponding receptors on the stem-cells. Application of α-gal nanoparticles to skin wounds of anti-Gal producing mice results in decrease in healing time by half. Furthermore, α-gal nanoparticles treated wounds restore the normal structure of the injured skin without fibrosis or scar formation. Similarly, in a mouse model of occlusion/reperfusion myocardial-infarction, near complete regeneration after intramyocardial injection of α-gal nanoparticles was demonstrated, whereas hearts injected with saline display ~20% fibrosis and scar formation of the left ventricular wall. It is suggested that recruitment of stem-cells following anti-Gal/α-gal nanoparticles interaction in injured tissues may result in induction of localized regeneration facilitated by conducive microenvironments generated by pro-reparative macrophage secretions and “cues” provided by the extracellular matrix in the injury site.
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16
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The Complement System, Aging, and Aging-Related Diseases. Int J Mol Sci 2022; 23:ijms23158689. [PMID: 35955822 PMCID: PMC9369321 DOI: 10.3390/ijms23158689] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/03/2022] [Accepted: 08/03/2022] [Indexed: 12/10/2022] Open
Abstract
The complement system is a part of the immune system and consists of multiple complement components with biological functions such as defense against pathogens and immunomodulation. The complement system has three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Increasing evidence indicates that the complement system plays a role in aging. Complement plays a role in inflammatory processes, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathways. In addition, the complement system plays a significant role in aging-related diseases, including Alzheimer’s disease, age-related macular degeneration, and osteoarthritis. However, the effect of complement on aging and aging-related diseases is still unclear. Thus, a better understanding of the potential relationship between complement, aging, and aging-related diseases will provide molecular targets for treating aging, while focusing on the balance of complement in during treatment. Inhibition of a single component does not result in a good outcome. In this review, we discussed the research progress and effects of complement in aging and aging-related diseases.
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17
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Li Y, Palmer A, Lupu L, Huber-Lang M. Inflammatory response to the ischaemia-reperfusion insult in the liver after major tissue trauma. Eur J Trauma Emerg Surg 2022; 48:4431-4444. [PMID: 35831749 DOI: 10.1007/s00068-022-02026-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Polytrauma is often accompanied by ischaemia-reperfusion injury to tissues and organs, and the resulting series of immune inflammatory reactions are a major cause of death in patients. The liver is one of the largest organs in the body, a characteristic that makes it the most vulnerable organ after multiple injuries. In addition, the liver is an important digestive organ that secretes a variety of inflammatory mediators involved in local as well as systemic immune inflammatory responses. Therefore, this review considers the main features of post-traumatic liver injury, focusing on the immuno-pathophysiological changes, the interactions between liver organs, and the principles of treatment deduced. METHODS We focus on the local as well as systemic immune response involving the liver after multiple injuries, with emphasis on the pathophysiological mechanisms. RESULTS An overview of the mechanisms underlying the pathophysiology of local as well as systemic immune responses involving the liver after multiple injuries, the latest research findings, and the current mainstream therapeutic approaches. CONCLUSION Cross-reactivity between various organs and cascade amplification effects are among the main causes of systemic immune inflammatory responses after multiple injuries. For the time being, the pathophysiological mechanisms underlying this interaction remain unclear. Future work will continue to focus on identifying potential signalling pathways as well as target genes and intervening at the right time points to prevent more severe immune inflammatory responses and promote better and faster recovery of the patient.
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Affiliation(s)
- Yang Li
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Annette Palmer
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Ludmila Lupu
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
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18
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Sehring IM, Mohammadi HF, Haffner-Luntzer M, Ignatius A, Huber-Lang M, Weidinger G. Zebrafish fin regeneration involves generic and regeneration-specific osteoblast injury responses. eLife 2022; 11:77614. [PMID: 35748539 PMCID: PMC9259016 DOI: 10.7554/elife.77614] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.
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Affiliation(s)
| | | | | | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, University Hospital Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm, Germany
| | - Gilbert Weidinger
- Institute of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany
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19
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Garg V, Chandanala S, David-Luther M, Govind M, Prasad RR, Kumar A, Prasanna SJ. The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective. Front Cell Dev Biol 2022; 10:793694. [PMID: 35198558 PMCID: PMC8858808 DOI: 10.3389/fcell.2022.793694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field.
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Irfan M, Kim JH, Druzinsky RE, Ravindran S, Chung S. Complement C5aR/LPS-induced BDNF and NGF modulation in human dental pulp stem cells. Sci Rep 2022; 12:2042. [PMID: 35132159 PMCID: PMC8821590 DOI: 10.1038/s41598-022-06110-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Stem cells with the ability to differentiate into a variety of cells and secrete nerve regeneration factors have become an emerging option in nerve regeneration. Dental pulp stem cells (DPSCs) appear to be a good candidate for nerve regeneration given their accessibility, neural crest origin, and neural repair qualities. We have recently demonstrated that the complement C5a system, which is an important mediator of inflammation and tissue regeneration, is activated by lipoteichoic acid-treated pulp fibroblasts, and governs the production of brain-derived nerve growth factor (BDNF). This BDNF secretion promotes neurite outgrowth towards the injury site. Here, we extend our observation to DPSCs and compare their neurogenic ability to bone marrow-derived mesenchymal stem cells (BM-MSCs) under inflammatory stimulation. Our ELISA and immunostaining data demonstrate that blocking the C5a receptor (C5aR) reduced BDNF production in DPSCs, while treatment with C5aR agonist increased the BDNF expression, which suggests that C5aR has a positive regulatory role in the BDNF modulation of DPSCs. Inflammation induced by lipopolysaccharide (LPS) treatment potentiated this effect and is C5aR dependent. Most important, DPSCs produced significantly higher levels of C5aR-mediated BDNF compared to BM-MSCs. Taken together, our data reveal novel roles for C5aR and inflammation in modulation of BDNF and NGF in DPSCs.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Ji Hyun Kim
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Robert E Druzinsky
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA.
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21
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The role of complement C5a receptor in DPSC odontoblastic differentiation and in vivo reparative dentin formation. Int J Oral Sci 2022; 14:7. [PMID: 35087028 PMCID: PMC8795457 DOI: 10.1038/s41368-022-00158-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/18/2021] [Accepted: 12/28/2021] [Indexed: 12/20/2022] Open
Abstract
Therapeutic dentin regeneration remains difficult to achieve, and a majority of the attention has been given to anabolic strategies to promote dentinogenesis directly, whereas, the available literature is insufficient to understand the role of inflammation and inflammatory complement system on dentinogenesis. The aim of this study is to determine the role of complement C5a receptor (C5aR) in regulating dental pulp stem cells (DPSCs) differentiation and in vivo dentin regeneration. Human DPSCs were subjected to odontogenic differentiation in osteogenic media treated with the C5aR agonist and C5aR antagonist. In vivo dentin formation was evaluated using the dentin injury/pulp-capping model of the C5a-deficient and wild-type mice. In vitro results demonstrate that C5aR inhibition caused a substantial reduction in odontogenic DPSCs differentiation markers such as DMP-1 and DSPP, while the C5aR activation increased these key odontogenic genes compared to control. A reparative dentin formation using the C5a-deficient mice shows that dentin regeneration is significantly reduced in the C5a-deficient mice. These data suggest a positive role of C5aR in the odontogenic DPSCs differentiation and tertiary/reparative dentin formation. This study addresses a novel regulatory pathway and a therapeutic approach for improving the efficiency of dentin regeneration in affected teeth.
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22
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3'mRNA sequencing reveals pro-regenerative properties of c5ar1 during resolution of murine acetaminophen-induced liver injury. NPJ Regen Med 2022; 7:10. [PMID: 35087052 PMCID: PMC8795215 DOI: 10.1038/s41536-022-00206-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022] Open
Abstract
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
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23
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Liu J, Wei X, Hu J, Tan X, Kang X, Gao L, Li N, Shi X, Yuan M, Hu W, Liu M. Different concentrations of C5a affect human dental pulp mesenchymal stem cells differentiation. BMC Oral Health 2021; 21:470. [PMID: 34560867 PMCID: PMC8464103 DOI: 10.1186/s12903-021-01833-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 09/16/2021] [Indexed: 11/16/2022] Open
Abstract
Background During the process of deep decay, when decay approaches the pulp, an immune response is triggered inside the pulp, which activates the complement cascade. The effect of complement component 5a (C5a) on the differentiation of dental pulp mesenchymal stem cells (DPSCs) is related to dentin reparation. The aim of the present study was to stimulate DPSCs with different concentrations of C5a and evaluate the differentiation of odontoblasts using dentin sialoprotein (DSP). Methods DPSCs were divided into the following six groups: (i) Control; (ii) DPSCs treated with 50 ng/ml C5a; (iii) DPSCs treated with 100 ng/ml C5a; (iv) DPSCs treated with 200 ng/ml C5a; (v) DPSCs treated with 300 ng/ml C5a; and (vi) DPSCs treated with 400 ng/ml C5a. Flow cytometry and multilineage differentiation potential were used to identify DPSCs. Mineralization induction, Real-time PCR and Western blot were conducted to evaluate the differentiation of odontoblast in the 6 groups. Result DPSCs can express mesenchymal stem cell markers, including CD105, CD90, CD73 and, a less common marker, mesenchymal stromal cell antigen-1. In addition, DPSCs can differentiate into adipocytes, neurocytes, chondrocytes and odontoblasts. All six groups formed mineralized nodules after 28 days of culture. Reverse transcription-quantitative PCR and western blotting indicated that the high concentration C5a groups expressed higher DSP levels and promoted DPSC differentiation, whereas the low concentration C5a groups displayed an inhibitory effect. Conclusion In this study, the increasing concentration of C5a, which accompanies the immune process in the dental pulp, has demonstrated an enhancing effect on odontoblast differentiation at higher C5a concentrations in vitro.
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Affiliation(s)
- Jie Liu
- Department of Radiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Xiaoling Wei
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University and The Key Laboratory of Myocardial Ischemia Ministry of Education, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Junlong Hu
- Plastic Surgery Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xiaohan Tan
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University and The Key Laboratory of Myocardial Ischemia Ministry of Education, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Xiaocui Kang
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Li Gao
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Ning Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University and The Key Laboratory of Myocardial Ischemia Ministry of Education, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Xin Shi
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Mengtong Yuan
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Harbin, 150086, Heilongjiang, People's Republic of China
| | - Weiping Hu
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Harbin, 150086, Heilongjiang, People's Republic of China.
| | - Mingyue Liu
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University and The Key Laboratory of Myocardial Ischemia Ministry of Education, No. 246, Xuefu Road, Harbin, 150086, Heilongjiang, People's Republic of China.
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24
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Santiesteban-Lores LE, Carneiro MC, Isaac L, Bavia L. Complement System in Alcohol-Associated Liver Disease. Immunol Lett 2021; 236:37-50. [PMID: 34111475 DOI: 10.1016/j.imlet.2021.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022]
Abstract
Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.
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Affiliation(s)
| | | | - Lourdes Isaac
- Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - Lorena Bavia
- Institute of Biomedical Sciences, University of São Paulo, Brazil.
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25
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Nording H, Baron L, Haberthür D, Emschermann F, Mezger M, Sauter M, Sauter R, Patzelt J, Knoepp K, Nording A, Meusel M, Meyer-Saraei R, Hlushchuk R, Sedding D, Borst O, Eitel I, Karsten CM, Feil R, Pichler B, Erdmann J, Verschoor A, Chavakis E, Chavakis T, von Hundelshausen P, Köhl J, Gawaz M, Langer HF. The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nat Commun 2021; 12:3352. [PMID: 34099640 PMCID: PMC8185003 DOI: 10.1038/s41467-021-23499-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - David Haberthür
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Frederic Emschermann
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Matthias Mezger
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Reinhard Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Johannes Patzelt
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Kai Knoepp
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Anne Nording
- grid.10392.390000 0001 2190 1447Institute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany
| | - Moritz Meusel
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Roza Meyer-Saraei
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Ruslan Hlushchuk
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Daniel Sedding
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Oliver Borst
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Ingo Eitel
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Christian M. Karsten
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Robert Feil
- grid.10392.390000 0001 2190 1447Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Bernd Pichler
- grid.10392.390000 0001 2190 1447Institute for Preclinical Imaging, Eberhard Karls University, Tübingen, Germany
| | - Jeanette Erdmann
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.4562.50000 0001 0057 2672Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Admar Verschoor
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Emmanouil Chavakis
- grid.411088.40000 0004 0578 8220Department for Internal Medicine III/Cardiology, University Hospital of the Johann-Wolfgang Goethe University, Frankfurt am Main, Germany
| | - Triantafyllos Chavakis
- grid.4488.00000 0001 2111 7257Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Philipp von Hundelshausen
- grid.5252.00000 0004 1936 973XInstitute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany
| | - Jörg Köhl
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany ,grid.239573.90000 0000 9025 8099Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Meinrad Gawaz
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
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26
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Zwicky SN, Stroka D, Zindel J. Sterile Injury Repair and Adhesion Formation at Serosal Surfaces. Front Immunol 2021; 12:684967. [PMID: 34054877 PMCID: PMC8160448 DOI: 10.3389/fimmu.2021.684967] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 04/23/2021] [Indexed: 12/19/2022] Open
Abstract
Most multicellular organisms have a major body cavity containing vital organs. This cavity is lined by a mucosa-like serosal surface and filled with serous fluid which suspends many immune cells. Injuries affecting the major body cavity are potentially life-threatening. Here we summarize evidence that unique damage detection and repair mechanisms have evolved to ensure immediate and swift repair of injuries at serosal surfaces. Furthermore, thousands of patients undergo surgery within the abdominal and thoracic cavities each day. While these surgeries are potentially lifesaving, some patients will suffer complications due to inappropriate scar formation when wound healing at serosal surfaces defects. These scars called adhesions cause profound challenges for health care systems and patients. Therefore, reviewing the mechanisms of wound repair at serosal surfaces is of clinical importance. Serosal surfaces will be introduced with a short embryological and microanatomical perspective followed by a discussion of the mechanisms of damage recognition and initiation of sterile inflammation at serosal surfaces. Distinct immune cells populations are free floating within the coelomic (peritoneal) cavity and contribute towards damage recognition and initiation of wound repair. We will highlight the emerging role of resident cavity GATA6+ macrophages in repairing serosal injuries and compare serosal (mesothelial) injuries with injuries to the blood vessel walls. This allows to draw some parallels such as the critical role of the mesothelium in regulating fibrin deposition and how peritoneal macrophages can aggregate in a platelet-like fashion in response to sterile injury. Then, we discuss how serosal wound healing can go wrong, causing adhesions. The current pathogenetic understanding of and potential future therapeutic avenues against adhesions are discussed.
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Affiliation(s)
- Simone N Zwicky
- Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Deborah Stroka
- Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Joel Zindel
- Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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27
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A/J mice are more susceptible than C57BL/6 to acetaminophen-induced hepatotoxicity. J Pharmacol Toxicol Methods 2021; 108:106960. [PMID: 33766729 DOI: 10.1016/j.vascn.2021.106960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/02/2021] [Accepted: 02/28/2021] [Indexed: 11/20/2022]
Abstract
Acetaminophen (APAP) is commonly used to treat fever and pain. However, when in overdose is the predominant cause of hepatotoxicity. Despite advances in understanding the mechanisms of APAP-induced hepatotoxicity, the management of acute liver failure remains a challenge. Thus, more relevant experimental models are crucial to provide a better understanding of this condition. The aim of this study is to evaluate the effect of APAP-induced hepatotoxicity on A/J mice using C57BL/6 as reference experimental model. Eight- to ten-week-old male A/J and C57BL/6 mice were treated with APAP (300 or 500 mg/kg) by intraperitoneal injection. After 24 h total blood leukocyte counting, plasma levels of alanine amino transferase (ALT) and aspartate amino transferase (AST), histopathological analysis of liver, lung and kidney were evaluated. A/J mice presented reduction in circulating leukocytes concomitant with the increase in plasma levels of ALT and AST, and liver necrosis when treated with 300 and 500 mg/kg of APAP. C57BL/6 mice presented similar results only with 500 mg/kg of APAP. Our results show that A/J mice have a marked susceptibility to the effects of APAP and could be considered as an experimental model to study APAP-induced toxicity.
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28
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Hu ZG, Zhou Y, Lin CJ, Yuan GD, He SQ. Emerging recognition of the complement system in hepatic ischemia/reperfusion injury, liver regeneration and recovery (Review). Exp Ther Med 2021; 21:223. [PMID: 33603832 PMCID: PMC7851628 DOI: 10.3892/etm.2021.9654] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 11/26/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is a result of the ischemic cascade and may occur in the settings of liver trauma, resection and transplantation. Components of the complement system have been indicated to be mediators of hepatic IRI and regulators of liver regeneration. As such, their potential to mediate both beneficial and harmful effects render them key targets for therapy. In the present study, the mechanisms of complement mediating hepatic IRI were discussed with a focus on the different functions of complement in hepatic injury and liver recovery, and an explanation for this apparent paradox is provided, i.e. that the complement products C3a and C5a have an important role in liver damage; however, C3a and C5a are also necessary for liver regeneration. Furthermore, situated at the end of the complement activation cascade, the membrane attack complex is crucial in hepatic IRI and inhibiting the complex with a site-targeted murine complement inhibitor, complement receptor 2-CD59, may improve liver regeneration after partial hepatectomy, even when hepatectomy is combined with ischemia and reperfusion.
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Affiliation(s)
- Zhi-Gao Hu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Zhou
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Cheng-Jie Lin
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Guan-Dou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Song-Qing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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29
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Vandendriessche S, Cambier S, Proost P, Marques PE. Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front Cell Dev Biol 2021; 9:624025. [PMID: 33644062 PMCID: PMC7905230 DOI: 10.3389/fcell.2021.624025] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.
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Affiliation(s)
- Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Pedro E Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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30
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Smole U, Kratzer B, Pickl WF. Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces. Eur J Immunol 2020; 50:624-642. [PMID: 32246830 PMCID: PMC7216992 DOI: 10.1002/eji.201847811] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/25/2020] [Accepted: 03/31/2020] [Indexed: 01/08/2023]
Abstract
Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membrane‐bound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C‐reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H‐ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C‐reactive protein and pentraxin 3; L‐ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar–air interface.
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Affiliation(s)
- Ursula Smole
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Bernhard Kratzer
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Winfried F. Pickl
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
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Bergmann M, Jeanneau C, Giraud T, Richard G, About I. Complement activation links inflammation to dental tissue regeneration. Clin Oral Investig 2020; 24:4185-4196. [PMID: 33051813 DOI: 10.1007/s00784-020-03621-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/01/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Complement is an efficient plasma immune surveillance system. It initiates inflammation by inducing vascular modifications and attracting immune cells expressing Complement receptors. Investigating Complement receptors in non-immune cells pointed out Complement implication in the regeneration of tissue such as liver, skin, or bone. This review will shed the light on Complement implication in the initial steps of dental tissue regeneration. MATERIALS AND METHODS Review of literature was conducted on Complement local expression and implication in oral tissue regeneration in vivo and in vitro. RESULTS Recent data reported expression of Complement receptors and soluble proteins in dental tissues. Cultured pulp fibroblasts secrete all Complement components. Complement C3b and MAC have been shown to control bacteria growth in the dental pulp while C3a and C5a are involved in the initial steps of pulp regeneration. Indeed, C3a induces pulp stem cell/fibroblast proliferation, and fibroblast recruitment, while C5a induces neurite growth, guides stem cell recruitment, and odontoblastic differentiation. Similarly, cultured periodontal ligament cells produce C5a which induces bone marrow mesenchymal stem cell recruitment. CONCLUSIONS Overall, this review highlights that local Complement synthesis in dental tissues plays a major role, not only in eliminating bacteria but also in the initial steps of dental tissue regeneration, thus providing a link between dental tissue inflammation and regeneration. CLINICAL RELEVANCE Complement provides an explanation for understanding why inflammation preceeds regeneration. This may also provide a biological rational for understanding the reported success conservative management of mature permanent teeth with carious pulp exposure.
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Affiliation(s)
- Madison Bergmann
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France
| | | | - Thomas Giraud
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France
- APHM, Hôpital Timone Marseille, Service d'Odontologie, Marseille, France
| | | | - Imad About
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France.
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Yoshida K, Kawakami K, Abe G, Tamura K. Zebrafish can regenerate endoskeleton in larval pectoral fin but the regenerative ability declines. Dev Biol 2020; 463:110-123. [PMID: 32422142 DOI: 10.1016/j.ydbio.2020.04.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 01/12/2023]
Abstract
We show for the first time endoskeletal regeneration in the developing pectoral fin of zebrafish. The developing pectoral fin contains an aggregation plate of differentiated chondrocytes (endochondral disc; primordium for endoskeletal components, proximal radials). The endochondral disc can be regenerated after amputation in the middle of the disc. The regenerated disc sufficiently forms endoskeletal patterns. Early in the process of regenerating the endochondral disc, epithelium with apical ectodermal ridge (AER) marker expression rapidly covers the amputation plane, and mesenchymal cells start to actively proliferate. Taken together with re-expression of a blastema marker gene, msxb, and other developmental genes, it is likely that regeneration of the endochondral disc recaptures fin development as epimorphic limb regeneration does. The ability of endoskeletal regeneration declines during larval growth, and adult zebrafish eventually lose the ability to regenerate endoskeletal components such that amputated endoskeletons become enlarged. Endoskeletal regeneration in the zebrafish pectoral fin will serve as a new model system for successful appendage regeneration in mammals.
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Affiliation(s)
- Keigo Yoshida
- Department of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku University, Aobayama Aoba-ku, Sendai, 980-8578, Japan
| | - Koichi Kawakami
- Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Shizuoka, 411-8540, Japan; Department of Genetics, The Graduate University for Advanced Studies, SOKENDAI, Mishima, Shizuoka, 411-8540, Japan
| | - Gembu Abe
- Department of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku University, Aobayama Aoba-ku, Sendai, 980-8578, Japan
| | - Koji Tamura
- Department of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku University, Aobayama Aoba-ku, Sendai, 980-8578, Japan.
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Maisha N, Coombs T, Lavik E. Development of a Sensitive Assay to Screen Nanoparticles in vitro for Complement Activation. ACS Biomater Sci Eng 2020; 6:4903-4915. [PMID: 33313396 DOI: 10.1021/acsbiomaterials.0c00722] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nanomedicines are often recognized by the innate immune system as a threat, leading to unwanted clearance due to complement activation. This adverse reaction not only alters the bioavailability of the therapeutic but can also cause cardiopulmonary complications and death in a portion of the population. There is a need for tools for assessing complement response in the early stage of development of nanomedicines. Currently, quantifying complement-mediated response in vitro is limited due to differences between in vitro and in vivo responses for the same precursors, differences in the complement systems in different species, and lack of highly sensitive tools for quantifying the changes. Hence, we have worked on developing complement assay conditions and sample preparation techniques that can be highly sensitive in assessing the complement-mediated response in vitro mimicking the in vivo activity. We are screening the impact of incubation time, nanoparticle dosage, anticoagulants, and species of the donor in both blood and blood components. We have validated the optimal assay conditions by replicating the impact of zeta potential seen in vivo on complement activation in vitro. As observed in our previous in vivo studies, where nanoparticles with neutral zeta-potential were able to suppress complement response, the change in the complement biomarker was least for the neutral nanoparticles as well through our developed guidelines. These assay conditions provide a vital tool for assessing the safety of intravenously administered nanomedicines.
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Affiliation(s)
- Nuzhat Maisha
- Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, Piscataway Territories
| | - Tobias Coombs
- Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, Piscataway Territories
| | - Erin Lavik
- Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, Piscataway Territories
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Huang J, Cui Z, Gu QH, Zhang YM, Qu Z, Wang X, Wang F, Cheng XY, Meng LQ, Liu G, Zhao MH. Complement activation profile of patients with primary focal segmental glomerulosclerosis. PLoS One 2020; 15:e0234934. [PMID: 32569286 PMCID: PMC7307932 DOI: 10.1371/journal.pone.0234934] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/04/2020] [Indexed: 11/25/2022] Open
Abstract
Background Studies on adriamycin mice model suggest complement system is activated and together with IgM contributes to the glomerular injury of primary focal segmental glomerulosclerosis (FSGS). We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes. Here we examined the plasma and urinary complement profile of patients with primary FSGS, aiming to investigate the complement participation in FSGS pathogenesis. Methods Seventy patients with biopsy-proven primary FSGS were enrolled. The plasma and urinary levels of C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb were determined by commercial ELISA kits. Results The levels of C3a, C5a and C5b-9 in plasma and urine of FSGS patients were significantly higher than those in normal controls. The plasma and urinary levels of C5b-9 were positively correlated with urinary protein, renal dysfunction and interstitial fibrosis. The plasma C5a levels were positively correlated with the proportion of segmental sclerotic glomeruli. The urinary levels of Bb were elevated, positively correlated with C3a and C5b-9 levels, renal dysfunction, and interstitial fibrosis. The plasma C1q level was significantly decreased, and negatively correlated with urinary protein excretion. Urinary Bb level was a risk factor for no remission (HR = 3.348, 95% CI 1.264–8.870, P = 0.015) and ESRD (HR = 2.323, 95% CI 1.222–4.418, P = 0.010). Conclusion In conclusion, our results identified the systemic activation of complement in human primary FSGS, possibly via the classical and alternative pathway. The activation of complement system was partly associated with the clinical manifestations, kidney pathological damage, and renal outcomes.
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Affiliation(s)
- Jing Huang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
- * E-mail:
| | - Qiu-hua Gu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Yi-miao Zhang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Zhen Qu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Xin Wang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Fang Wang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Xu-yang Cheng
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Li-qiang Meng
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Gang Liu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Ming-hui Zhao
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
- Peking-Tsinghua Center for Life Sciences, Beijing, PR China
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Shi JH, Line PD. Hallmarks of postoperative liver regeneration: An updated insight on the regulatory mechanisms. J Gastroenterol Hepatol 2020; 35:960-966. [PMID: 31782974 DOI: 10.1111/jgh.14944] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/14/2019] [Accepted: 11/26/2019] [Indexed: 12/12/2022]
Abstract
Performance and advances in liver surgery makes remarkable progress of the understanding of liver regeneration. Liver regeneration after liver resection has been widely researched, and the underlying mechanism mostly concerns proliferation of hepatocytes and the influence by inflammation through activation of Kupffer cells and the other parenchymal cells, the second regenerative pathway by hepatic progenitor cells (HPCs), inducing angiogenesis, remodeling of a extracellular matrix (ECM), and termination mechanisms. New clinical surgeries and the updated multiomics analysis are exploiting the remarkable progress, especially in immune regulation and metabolic process of two emerging hallmarks. This review briefly represents a systemic outline of eight hallmarks, including hepatocyte proliferation, contribution of hepatic progenitor cells, inducing angiogenesis, reprogramming of the extracellular matrix, apoptosis and termination of proliferation, inflammation, immune and metabolic regulation, which are set as organizing characteristics of postoperative liver regeneration and future directions of refining treatment targets.
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Affiliation(s)
- Ji-Hua Shi
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Pål-Dag Line
- Department of Transplantation Medicine, Institute of Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Li Q, Lu Q, Zhu MQ, Huang C, Yu KK, Huang YX, Zhao X, Luo XG, Zheng JM. Lower level of complement component C3 and C3a in the plasma means poor outcome in the patients with hepatitis B virus related acute-on-chronic liver failure. BMC Gastroenterol 2020; 20:106. [PMID: 32293297 PMCID: PMC7158068 DOI: 10.1186/s12876-020-01258-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/31/2020] [Indexed: 12/17/2022] Open
Abstract
Background The purpose of this study is to investigate whether or not the complement system is systemically activated and to specify the clinical and prognostic implications of its components during hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF). Methods Blood samples were taken from twenty-seven patients diagnosed with HBV-ACLF, twenty-five patients diagnosed with chronic hepatitis B but without liver failure (CHB), and nine healthy volunteers (the control group). Plasma complement components were measured with Enzyme-linked immunosorbent assay. Correlative analysis were assessed between the levels of complement components and the liver failure related index. Results The concentrations of C3 was 6568 μg/ml in the HBV-ACLF group, 8916 μg/ml in the CHB group and 15,653 μg/ml in the control group, respectively (P < 0.05). The concentrations of C3a was 852 ng/ml in the HBV-ACLF group, 1008 ng/ml in the CHB group and 1755 ng/ml in the control group, respectively (P < 0.05). The concentrations of C1q was 50,509 ng/ml in the HBV-ACLF group, 114,640 ng/ml in the CHB group and 177,001 ng/ml in the control group, respectively (P < 0.05). The concentrations of C1q, C3, C3a, C4, C4a and sC5b-9 were significantly higher in the control group than those in the HBV-ACLF group (3.5, 2.4, 2.1, 1.4, 1.3 and 6.0 fold, respectively). However, there was no statistical significance of the differences in the plasma concentrations of mannose binding lectin and factor B between the HBV-ACLF group and control group. The levels of C3 and C3a were inversely correlated with MELDs or CLIF-C OFs (P < 0.05). Conclusions Our analysis demonstrated that the activation of the classical pathway mediated by C1q may play an important role in the pathogenesis of HBV-ACLF. Furthermore, the plasma levels of C3 and C3a may be potential novel biomarkers in predicting the outcome of HBV-ACLF.
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Affiliation(s)
- Qian Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Qing Lu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Chong Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Kang-Kang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Yu-Xian Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China
| | - Xu Zhao
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, China.,Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Xing-Guang Luo
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA
| | - Jian-Ming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, No.12 Wurumqi Middle Road, Jing'an district, Room 508, Shanghai, 200040, People's Republic of China.
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Goldberg BS, Ackerman ME. Antibody-mediated complement activation in pathology and protection. Immunol Cell Biol 2020; 98:305-317. [PMID: 32142167 DOI: 10.1111/imcb.12324] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/27/2020] [Accepted: 03/03/2020] [Indexed: 01/10/2023]
Abstract
Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.
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Affiliation(s)
| | - Margaret E Ackerman
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.,Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
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Abstract
Much of our knowledge regarding the interactions between epithelial tissues and the immune system has been gathered from animal models and co-cultures with cell lines. However, unique features of human cells cannot be modelled in mice, and cell lines are often transformed or genetically immortalized. Organoid technology has emerged as a powerful tool to maintain epithelial cells in a near-native state. In this Review, we discuss how organoids are being used in immunological research to understand the role of epithelial cell-immune cell interactions in tissue development and homeostasis, as well as in diseases such as cancer.
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Campoverde C, Milne DJ, Secombes CJ, Estévez A, Gisbert E, Andree KB. Gene expression analysis of the innate immune system during early rearing and weaning of meagre (Argyrosomus regius). FISH & SHELLFISH IMMUNOLOGY 2019; 94:819-832. [PMID: 31597086 DOI: 10.1016/j.fsi.2019.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/03/2019] [Accepted: 10/05/2019] [Indexed: 06/10/2023]
Abstract
The present study is the first report of some representative innate immune genes in meagre (Argyrosomus regius) larvae. This study has specifically focused on the growth period from hatching to the juvenile stage, a critical time in marine fish development when reliance on innate immune mechanisms are required for survival. We report molecular cloning of partial open reading frames and expression patterns for some innate immune genes (c3, cox2, met, lyzc, mxp, myd88, nod2, nod3). In addition, phylogenetic analyses of some of the sequences obtained was performed where confusion among closely allied isoforms may have existed. These results show the met isoform from meagre is met II, an isoform more similar to a homolog described in Larimichthys crocea; lysozyme (lyzc) corresponds to the c-type and NOD isoforms (nod2, nod3) separate into different clades confirming their distinctness within a common evolutionary history. Gene expression profiles of innate genes were investigated, for nine developmental stages, from 8 days post-hatching (dph) to 120 dph. Present results demonstrated that c3, cox2, met II, lyzc, mxp, myd88, nod2, and nod3 were expressed in all stages of larval development and displayed distinct expression profiles in separate tissues (kidney, spleen gut and gill). Moreover, expression patterns suggested theses innate immune genes may be influenced by feeding practices, i.e. switching from live prey (rotifer and Artemia) and weaning onto an inert commercial diet. In addition to evaluating changes in gene expression during early development, this study evaluated the modulation of gene expression by means of in vivo trials in juveniles that were stimulated with PAMPs (LPS, poly I:C, β-glucan). These results revealed significant changes in mRNA levels of target genes in the kidney, spleen, gut and gills. However, expression profiles differed in magnitude depending on the stimulant and/or tissue. These results are discussed in terms of their relevance and potential application in aquaculture practices.
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Affiliation(s)
| | - Douglas J Milne
- Scottish Fish Immunology Research Centre, University of Aberdeen, Zoology Building, Tillydrone Avenue, Aberdeen AB24 2TZ, Scotland, UK
| | - Christopher J Secombes
- Scottish Fish Immunology Research Centre, University of Aberdeen, Zoology Building, Tillydrone Avenue, Aberdeen AB24 2TZ, Scotland, UK
| | | | - Enric Gisbert
- IRTA, San Carlos de La Rápita, 43540, Tarragona, Spain
| | - Karl B Andree
- IRTA, San Carlos de La Rápita, 43540, Tarragona, Spain.
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Cytokine Profile in Early Infection by Leptospira interrogans in A/J Mice. J Immunol Res 2019; 2019:1892508. [PMID: 31687410 PMCID: PMC6800925 DOI: 10.1155/2019/1892508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/07/2019] [Accepted: 06/22/2019] [Indexed: 12/28/2022] Open
Abstract
Leptospirosis is considered a neglected disease with an estimated more than one million cases every year. Since rodents are at the same time the main reservoir and generally asymptomatic to Leptospira infection, understanding why some animal species are resistant and others are susceptible to this infection would shed some light in how to control this important zoonosis. The innate immune response against Leptospira is mainly dependent on phagocytosis and activation of the Complement System. In this context, cytokines may drive the early control of infection and the adaptive response. Since the Complement System is important to eliminate leptospires in vivo, we investigated if Complement C5 in A/J mice would modulate the cytokine production during infection by Leptospira interrogans serovar Kennewicki type Pomona Fromm (LPF). Thus, our aim was to investigate the systemic levels of pro- and anti-inflammatory cytokines during Leptospira infection in the blood, liver, lung, and kidney on the third and sixth days of infection in A/J C5+/+ and A/J C5-/- mice. Blood levels of TNF-α, IL-6, IFN-γ, and MCP-1 reached a peak on the third day. Although both mouse strains developed splenomegaly, similar histopathological alterations in the liver and the lung, levels of pro- and anti-inflammatory cytokines were different. A/J C5+/+ mice had higher levels of liver IL-10, IL-1β, IL-12p40, and IL-12p70 and kidney IL-1β, IL-12p40, and IL-12p70 on the sixth day of infection when compared to A/J C5-/- mice. Our results showed that in A/J genetic background, the Complement component C5 modulates a cytokine profile in the liver and kidney of infected mice, which may play a role in the control of disease progression.
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Zhang Y, Jin S. Mitigating placental injuries through up-regulating DAF in experimental APS mice: new mechanism of progesterone. Clin Exp Immunol 2019; 197:376-386. [PMID: 31091357 PMCID: PMC6693963 DOI: 10.1111/cei.13313] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2019] [Indexed: 01/06/2023] Open
Abstract
Anti-phospholipid syndrome (APS) is characterized by recurrent pathological pregnancy, arterial or venous thrombosis in the presence of anti-phospholipid antibody (aPL). Complement activation is recognized as an intermediate link leading to placental thrombosis and placental inflammation in APS model mice. Decay accelerating factor (DAF, CD55), MAC-inhibitory protein (MAC-IP, CD59) and membrane co-factor protein (MCP, CD46) are important complement inhibitory proteins (CIPs) highly expressed in normal placenta to curb excessive complement activation and its mediated injuries. Anti-β2 glycoprotein I (anti-β2GPI) antibody is an important aPL. We found that placental DAF and CD46 decreased in β2GPI passively immunized APS model mice, accompanied by C3 deposition, neutrophil infiltration and increased proinflammatory cytokine levels detected in its placenta. Progesterone supplement can up-regulate DAF but not CD46 expression, curb C3 activation and decrease proinflammatory cytokines levels to reduce fetal loss frequency. Progesterone receptor antagonist (mifepristone) or knock-down DAF with specific siRNA, above the protective effects of progesterone, were significantly weakened. Another sex hormone, oestrogen, has no significant effect on placental DAF and C3 contents and fetal loss frequency in the APS mice model. This may be an important mechanism by which progesterone induces maternal-fetal immune tolerance. At the same time, it may provide evidence for the use of progesterone in APS abortion patients.
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Affiliation(s)
- Y. Zhang
- Department of Traditional Chinese MedicineMaternal and Child Health Hospital of Hubei ProvinceHubeiChina
| | - S. Jin
- Department of Traditional Chinese MedicineMaternal and Child Health Hospital of Hubei ProvinceHubeiChina
- First Clinical Medical CollegeHubei University of Chinese MedicineHubeiChina
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Thorgersen EB, Barratt‐Due A, Haugaa H, Harboe M, Pischke SE, Nilsson PH, Mollnes TE. The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology 2019; 70:725-736. [PMID: 30653682 PMCID: PMC6771474 DOI: 10.1002/hep.30508] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 01/10/2019] [Indexed: 12/20/2022]
Abstract
The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.
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Affiliation(s)
- Ebbe Billmann Thorgersen
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Department of Gastroenterological SurgeryThe Norwegian Radium Hospital, Oslo University HospitalOsloNorway
| | - Andreas Barratt‐Due
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway
| | - Håkon Haugaa
- Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway,Lovisenberg Diaconal University CollegeOsloNorway
| | - Morten Harboe
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway
| | - Søren Erik Pischke
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway
| | - Per H. Nilsson
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Linnaeus Centre for Biomaterials ChemistryLinnaeus UniversityKalmarSweden
| | - Tom Eirik Mollnes
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Reserach Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TRECUniversity of TromsøTromsøNorway,Centre of Molecular Inflammation ResearchNorwegian University of Science and TechnologyTrondheimNorway
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Liu M, Mu H, Peng W, Zhao L, Hu W, Jiang Z, Gao L, Cao X, Li N, Han J. Time-dependent C5a and C5aR expression in dental pulp cells following stimulation with LTA and LPS. Int J Mol Med 2019; 44:823-834. [PMID: 31257457 PMCID: PMC6657968 DOI: 10.3892/ijmm.2019.4246] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/11/2019] [Indexed: 11/25/2022] Open
Abstract
Clinically, deep decay can lead to inflammation in the dental pulp. Apart from the use of various materials to sooth the inflamed pulp, there is currently no adequate treatment, and the gold standard, calcium hydroxide, that is used to cover the dentin/pulp, has limited effect. Sometimes the pulp will remain infected and cause pulpitis, and ultimately, the pulp will need to be removed. The first principle of oral treatment is to protect the pulp. Therefore, it is necessary to study the immune response and regeneration of pulp cells in conditions of deep decay. Of the terminal complement system proteins, complement 5a (C5a) has the most potent effect compared to complement 3a (C3a) and complement 4a (C4a). C5a is 20- to 2,500-fold stronger than C3a and C4a. The purpose of this study was to elucidate the association between C5a, secreted by complement activation, and the duration of inflammation. Another key goal was to detect the expression of C5a and its receptor, complement 5a receptor (C5aR). To this end, the cells were divided into 4 groups as per stimulation with lipoteichoic acid (LTA) or lipopolysaccharide (LPS) as follows: i) The 1 µg/ml LTA group; ii) the 1 µg/ml LPS group; iii) the 1 µg/ml LTA and 1 µg/ml LPS group; and iv) the PBS-only group, which served as a control. There were 5 time points for all 4 groups: 1, 2, 3, 5 and 7 days. Reverse transcription-quantitative polymerase chain reaction was used to detect the gene expression levels of C5a, C5aR and interleukin (IL)-6 at different time points. Western blot analyses was carried out to detect the expression of C5aR. Transmission electron microscopy was also conducted to assess the ultra-structural features of dental pulp cells. The gene expression trends of C5a and C5aR mRNA were identical. C5a and C5aR mRNA was highly expressed on the second day of LTA or LPS stimulation. However, in the LTA and LPS co-stimulation group, C5a and C5aR mRNA were highly expressed on both the first and second day, with higher levels on the second day. IL-6 expression decreased as time progressed in the LTA only and in the LTA + LPS co-stimulation groups. However, a peak in its expression was observed on the second day in the LPS group. On the whole, this study demonstrates that a 1 µg/ml concentration of LTA and LPS stimulates human dental pulp cells to activate the expression of C5a.
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Affiliation(s)
- Mingyue Liu
- Department of Prosthodontics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Haibin Mu
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Wenting Peng
- Department of Stomatology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Lin Zhao
- Department of Stomatology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Weiping Hu
- Department of Prosthodontics, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Zhuling Jiang
- Department of Oral Implantology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Li Gao
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xiaofang Cao
- Department of Endodontics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ning Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Jingying Han
- Department of Orthodontics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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44
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Zhou H, Hara H, Cooper DK. The complex functioning of the complement system in xenotransplantation. Xenotransplantation 2019; 26:e12517. [PMID: 31033064 PMCID: PMC6717021 DOI: 10.1111/xen.12517] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 03/15/2019] [Accepted: 03/22/2019] [Indexed: 12/25/2022]
Abstract
The role of complement in xenotransplantation is well-known and is a topic that has been reviewed previously. However, our understanding of the immense complexity of its interaction with other constituents of the innate immune response and of the coagulation, adaptive immune, and inflammatory responses to a xenograft is steadily increasing. In addition, the complement system plays a function in metabolism and homeostasis. New reviews at intervals are therefore clearly warranted. The pathways of complement activation, the function of the complement system, and the interaction between complement and coagulation, inflammation, and the adaptive immune system in relation to xenotransplantation are reviewed. Through several different mechanisms, complement activation is a major factor in contributing to xenograft failure. In the organ-source pig, the detrimental influence of the complement system is seen during organ harvest and preservation, for example, in ischemia-reperfusion injury. In the recipient, the effect of complement can be seen through its interaction with the immune, coagulation, and inflammatory responses. Genetic-engineering and other therapeutic methods by which the xenograft can be protected from the effects of complement activation are discussed. The review provides an updated source of reference to this increasingly complex subject.
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Affiliation(s)
- Hongmin Zhou
- Department of Cardiothoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David K.C. Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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van Zanden JE, Jager NM, Daha MR, Erasmus ME, Leuvenink HGD, Seelen MA. Complement Therapeutics in the Multi-Organ Donor: Do or Don't? Front Immunol 2019; 10:329. [PMID: 30873176 PMCID: PMC6400964 DOI: 10.3389/fimmu.2019.00329] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
Over the last decade, striking progress has been made in the field of organ transplantation, such as better surgical expertise and preservation techniques. Therefore, organ transplantation is nowadays considered a successful treatment in end-stage diseases of various organs, e.g. the kidney, liver, intestine, heart, and lungs. However, there are still barriers which prevent a lifelong survival of the donor graft in the recipient. Activation of the immune system is an important limiting factor in the transplantation process. As part of this pro-inflammatory environment, the complement system is triggered. Complement activation plays a key role in the transplantation process, as highlighted by the amount of studies in ischemia-reperfusion injury (IRI) and rejection. However, new insight have shown that complement is not only activated in the later stages of transplantation, but already commences in the donor. In deceased donors, complement activation is associated with deteriorated quality of deceased donor organs. Of importance, since most donor organs are derived from either brain-dead donors or deceased after circulatory death donors. The exact mechanisms and the role of the complement system in the pathophysiology of the deceased donor have been underexposed. This review provides an overview of the current knowledge on complement activation in the (multi-)organ donor. Targeting the complement system might be a promising therapeutic strategy to improve the quality of various donor organs. Therefore, we will discuss the complement therapeutics that already have been tested in the donor. Finally, we question whether complement therapeutics should be translated to the clinics and if all organs share the same potential complement targets, considering the physiological differences of each organ.
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Affiliation(s)
- Judith E. van Zanden
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Neeltina M. Jager
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Mohamed R. Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
| | - Michiel E. Erasmus
- Department of Thoracic Surgery, University Medical Center Groningen, Groningen, Netherlands
| | | | - Marc A. Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
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46
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Chmilewsky F, Liang R, Kanazawa M, About I, Cooper LF, George A. C5L2 Regulates DMP1 Expression during Odontoblastic Differentiation. J Dent Res 2019; 98:597-604. [PMID: 30702959 DOI: 10.1177/0022034518820461] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The presence of stem cells within the dental-pulp tissue as well as their differentiation into a new generation of functional odontoblast-like cells constitutes an important step of the dentin-pulp regeneration. Recent investigations demonstrated that the complement system activation participates in 2 critical steps of dentin-pulp regeneration: pulp progenitor's recruitment and pulp nerve sprouting. Surprisingly, its implication in odontoblastic differentiation has not been addressed yet. Since the complement receptor C5a receptor-like 2 (C5L2) is expressed by different stem cells, the aim of this study is to investigate if the dental pulp stem cells express C5L2 and if this receptor participates in odontoblastic differentiation. Immunohistochemistry performed on human third molar pulp sections showed a perivascular co-localization of the mesenchymal stem cell markers STRO1 and C5L2. In vitro immunofluorescent staining confirmed that hDPSCs express C5L2. Furthermore, we determined by real-time polymerase chain reaction that the expression of C5L2 is highly modulated in human dental pulp stem cells (hDPSCs) undergoing odontoblastic differentiation. Moreover, we showed that this odontogenesis-regulated expression of C5L2 is specifically potentiated by the proinflammatory cytokine TNFα. Using a C5L2-siRNA silencing strategy, we provide direct evidence that C5L2 constitutes a negative regulator of the dentinogenic marker DMP1 (dentin matrix protein 1) expression by hDPSCs. Our findings suggest a direct correlation between the odontoblastic differentiation and the level of C5L2 expression in hDPSCs and identify C5L2 as a negative regulator of DMP1 expression by hDPSCs during the odontoblastic differentiation and inflammation processes. This work is the first to demonstrate the involvement of C5L2 in the biological function of stem cells, provides an important knowledge in understanding odontoblastic differentiation of dental pulp stem cells, and may be useful in future dentin-pulp engineering strategies.
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Affiliation(s)
- F Chmilewsky
- 1 Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA
| | - R Liang
- 1 Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA
| | - M Kanazawa
- 1 Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA
| | - I About
- 2 Department of Oral Biology, Aix Marseille Université, Marseille, France
| | - L F Cooper
- 1 Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA
| | - A George
- 1 Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA
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Hansen CB, Willer A, Bayarri-Olmos R, Kemper C, Garred P. Expression of complement C3, C5, C3aR and C5aR1 genes in resting and activated CD4 + T cells. Immunobiology 2018; 224:307-315. [PMID: 30612786 DOI: 10.1016/j.imbio.2018.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 01/02/2023]
Abstract
Complement activation is traditionally thought to occur in the extracellular space. However, it has been suggested that complement proteins are activated and function at additional locations. T cells contain intracellular stores of C3 and C5 that can be cleaved into C3a and C5a and bind to intracellular receptors, which have been shown to be of vital importance for the differentiation and function of these cells. However, whether the origin of the complement proteins located within T cells is derived from endogenous produced complement or from an uptake dependent mechanism is unknown. The presence of intracellular C3 in T cells from normal donors was investigated by fluorescence microscopy and flow cytometry. Moreover, mRNA expression levels of several genes encoding for complement proteins with primary focus on C3, C3aR, C5 and C5aR1 during resting state and upon activation of CD4+ T cells were investigated by a quantitative PCR technique. Furthermore, the gene expression level was evaluated at different time points. We confirmed the presence of intracellular C3 protein in normal T-cells. However, we could not see any increase in mRNA levels using any activation strategy tested. On the contrary, we observed a slight increase in C3 and C5aR1 mRNA only in the non-activated T-cells compared to the activated T cells, and a decrease in the activated T-cells at different incubation time points. Our results show that there is a baseline intracellular expression of the complement C3, C5, C3aR and C5aR1 genes in normal CD4+ T cells, but that expression is not increased during T-cell activation, but rather down regulated. Thus, the pool of intracellular complement in CD4+ T cells may either be due to accumulated complement due low-grade expression or arise from the circulation from an uptake dependent mechanism, but these possibilities are not mutually exclusive.
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Affiliation(s)
- Cecilie Bo Hansen
- Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Denmark
| | - Anton Willer
- Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Denmark
| | - Rafael Bayarri-Olmos
- Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Denmark
| | - Claudia Kemper
- National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, MD, 20814, USA
| | - Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Denmark.
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Zhou J, Li J, Yu Y, Liu Y, Li H, Liu Y, Wang J, Zhang L, Lu X, Chen Z, Zuo D. Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment. J Leukoc Biol 2018; 105:177-186. [PMID: 30351498 DOI: 10.1002/jlb.3a0718-251r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/10/2018] [Accepted: 10/03/2018] [Indexed: 12/16/2022] Open
Abstract
Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4 ). Aggravated liver damage was shown in CCl4 -administrated MBL-/- mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl4 -induced liver injury was validated by administration of an MBL-expressing liver-specific adeno-associated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL-/- mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency.
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Affiliation(s)
- Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Junru Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Yu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Huifang Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunzhi Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jun Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Liyun Zhang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiao Lu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengliang Chen
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Proteomics, Southern Medical University, Guangzhou, Guangdong, China
| | - Daming Zuo
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Proteomics, Southern Medical University, Guangzhou, Guangdong, China.,Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.,Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, Bouchard K, Andrien B, Marozsan A, Wang Y, Tamburini P. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS One 2018; 13:e0195909. [PMID: 29649283 PMCID: PMC5897016 DOI: 10.1371/journal.pone.0195909] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 04/02/2018] [Indexed: 11/24/2022] Open
Abstract
Eculizumab, a monoclonal antibody (mAb) directed against complement protein C5, is considered to be the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. This study describes the generation and preclinical attributes of ALXN1210, a new long-acting anti-C5 mAb, obtained through select modifications to eculizumab to both largely abolish target-mediated drug disposition (TMDD) and increase recycling efficiency via the neonatal Fc receptor (FcRn). To attenuate the effect of TMDD on plasma terminal half-life (t1/2), histidine substitutions were engineered into the complementarity-determining regions of eculizumab to enhance the dissociation rate of the mAb:C5 complex in the acidic early endosome relative to the slightly basic pH of blood. Antibody variants with optimal pH-dependent binding to C5 exhibited little to no TMDD in mice in the presence of human C5. To further enhance the efficiency of FcRn-mediated recycling of the antibody, two additional substitutions were introduced to increase affinity for human FcRn. These substitutions yielded an additional doubling of the t½ of surrogate anti-mouse C5 antibodies with reduced TMDD in transgenic mice expressing the human FcRn. In conclusion, ALXN1210 is a promising new therapeutic candidate currently in clinical development for treatment of patients with PNH and atypical hemolytic uremic syndrome.
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Affiliation(s)
- Douglas Sheridan
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
- * E-mail:
| | - Zhao-Xue Yu
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Yuchun Zhang
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Rekha Patel
- Product Characterization, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Fang Sun
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Melissa A. Lasaro
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Keith Bouchard
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Bruce Andrien
- Early Assay Development, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Andre Marozsan
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Yi Wang
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
| | - Paul Tamburini
- Research, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, United States of America
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50
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Abstract
From its discovery in the late nineteenth century, as a 'complement' to the cellular immune response, the complement system has been widely affirmed as a powerful controller of innate and adaptive immune responses. In recent decades however, new roles for complement have been discovered, with multiple complement proteins now known to function in a broad array of non-immune systems. This includes during development, where complement exerts control over stem cell populations from fertilization and implantation throughout embryogenesis and beyond post-natal development. It is involved in processes as diverse as cell localisation, tissue morphogenesis, and the growth and refinement of the brain. Such physiological actions of complement have also been described in adult stem cell populations, with roles in proliferation, differentiation, survival, and regeneration. With such a broad range of complement functions now described, it is likely that current research only describes a fraction of the full reach of complement proteins. Here, we review how complement control of physiological cell processes has been harnessed in stem cell populations throughout both development and in adult physiology.
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Affiliation(s)
- Owen A Hawksworth
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia
| | - Liam G Coulthard
- School of Clinical Medicine, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Susanna Mantovani
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Wesley Medical Research, Auchenflower, Brisbane, Queensland, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia; Wesley Medical Research, Auchenflower, Brisbane, Queensland, Australia.
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