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1
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Thomas SA, Lajoie S. Complement's involvement in allergic Th2 immunity: a cross-barrier perspective. J Clin Invest 2025; 135:e188352. [PMID: 40309766 PMCID: PMC12043088 DOI: 10.1172/jci188352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025] Open
Abstract
Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.
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Affiliation(s)
- Sarah A. Thomas
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Stephane Lajoie
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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2
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Hirose T, Hotta K, Otsuka R, Seino KI. Mechanism and regulation of the complement activity in kidney xenotransplantation. Transplant Rev (Orlando) 2025; 39:100931. [PMID: 40233672 DOI: 10.1016/j.trre.2025.100931] [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: 10/15/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
Xenotransplantation is emerging as one of several potential solutions for addressing organ donor shortages, with significant progress bringing it closer to clinical application. However, challenges remain, particularly concerning complement system dysregulation caused by species differences, as well as xenoantigens and coagulopathy. Complement regulatory proteins expressed on endothelial cells of donor xenografts are less compatible with complement components in recipients. These difficulties contribute to hyperacute rejection, characterized by antibody-mediated complement activation that destroys the graft within 24 h. Moreover, because molecules are incompatible across different species, ischemia-reperfusion injury or infection can easily elicit complement activity via all three pathways, resulting in xenograft loss via complement-mediated vascular injury. Complement activity also stimulate innate and adaptive immune cells. To address this issue, genetic modifications in donor pigs and the development of novel medicines have been tested in preclinical models with promising results. Pigs modified to express human complement-regulating molecules such as CD46, CD55, and CD59 have shown longer kidney xenograft survivals over years in preclinical models with nonhuman primates, paving the way for clinical trials. Anti-complement component agents such as C1 esterase and C5 inhibitors have also been shown to increase xenograft survivals. This review examines the role of the complement system in kidney xenotransplantation, emphasizing new research and clinical trial advancements.
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Affiliation(s)
- Takayuki Hirose
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan.
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Ryo Otsuka
- Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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3
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He J, Yao Y, Wang R, Liu Y, Wan X, Wang H, Zhou Y, Wang W, Ma Y, Lv X. Enhanced renal ischemia/reperfusion injury repair potential of exosomes derived from B7-H1 high mesenchymal stem cells. Front Genet 2025; 16:1516626. [PMID: 40242472 PMCID: PMC12000007 DOI: 10.3389/fgene.2025.1516626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/11/2025] [Indexed: 04/18/2025] Open
Abstract
Two subgroups with high expression of B7-H1 and low expression of B7-H1 were successfully isolated from primitive human umbilical cord mesenchymal stem cells. And exosomes with high B7-H1 expression and low B7-H1 expression were successfully isolated. In comparison to the sham-operated group, mice in the IRI group demonstrated elevated serum levels of blood urea nitrogen (BUN) and serum creatinine (Scr), accompanied by a more pronounced degree of renal tissue damage. The administration of exosomes via the tail vein markedly accelerated the recovery of renal function in IRI mice, with the therapeutic effect beingmore pronounced in those treated with B7-H1high-Exo. Moreover RNA sequencing of mouse kidney treated with B7-H1high-Exo and B7-H1low-Exo showed that eight genes (C3, IRF7, AREG, CXCL10, Aldh1l2, Fnip2, Vcam1, St6galnac3) were involved in the pathophysiological process of ischemia-reperfusion injury. The in vitro and in vivo experiments showed that the expression level of C3 protein was significantly decreased, which indicated that B7-H1high-Exo played a therapeutic role by down-regulating C3.
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Affiliation(s)
- Jiahui He
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yawei Yao
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ruiyan Wang
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yujia Liu
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xingyu Wan
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Hao Wang
- Department of Day Surgery Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yuqiang Zhou
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Wenjing Wang
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yan Ma
- Department of Anaesthesia, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xinghua Lv
- Department of Day Surgery Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Yildiz R, Ganbold K, Sparman NZR, Rajbhandari P. Immune Regulatory Crosstalk in Adipose Tissue Thermogenesis. Compr Physiol 2025; 15:e70001. [PMID: 39921241 DOI: 10.1002/cph4.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 02/10/2025]
Abstract
Brown adipose tissue (BAT) and thermogenic beige fat within white adipose tissue (WAT), collectively known as adaptive thermogenic fat, dissipate energy as heat, offering promising therapeutic potential to combat obesity and metabolic disorders. The specific biological functions of these fat depots are determined by their unique interaction with the microenvironments, composed of immune cells, endothelial cells, pericytes, and nerve fibers. Immune cells residing in these depots play a key role in regulating energy expenditure and systemic energy homeostasis. The dynamic microenvironment of thermogenic fat depots is essential for maintaining tissue health and function. Immune cells infiltrate both BAT and beige WAT, contributing to their homeostasis and activation through intricate cellular communications. Emerging evidence underscores the importance of various immune cell populations in regulating thermogenic adipose tissue, though many remain undercharacterized. This review provides a comprehensive overview of the immune cells that regulate adaptive thermogenesis and their complex interactions within the adipose niche, highlighting their potential to influence metabolic health and contribute to therapeutic interventions for obesity and metabolic syndrome.
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Affiliation(s)
- Ramazan Yildiz
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Khatanzul Ganbold
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Njeri Z R Sparman
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Prashant Rajbhandari
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Disease Mechanism and Therapeutics Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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5
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Alibrandi S, Clemens A, Chun N. Complement and T cell activation in transplantation. Transplant Rev (Orlando) 2025; 39:100898. [PMID: 39615218 PMCID: PMC11710966 DOI: 10.1016/j.trre.2024.100898] [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: 08/14/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
The complement system plays a critical role in modulating adaptive T cell responses. Coordination of the proinflammatory signaling cascade and complement regulators permits efficient T cell priming and survival, while minimizing off-target damage to healthy host cells. In the context of transplantation, anti-donor T cell immunity remains a barrier to long term graft health and complement-targeted therapies have shown the potential to significantly improve patient outcomes. Here we will review our current understanding of complement-mediated T cell function and how these findings may be harnessed in organ transplantation.
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Affiliation(s)
- Sara Alibrandi
- Translational Transplant Research Center and Barbara T. Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, NY, USA; Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Angela Clemens
- Translational Transplant Research Center and Barbara T. Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, NY, USA
| | - Nicholas Chun
- Translational Transplant Research Center and Barbara T. Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, NY, USA.
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Liu G, He X, Zhao G, Lu Z. Complement regulation in tumor immune evasion. Semin Immunol 2024; 76:101912. [PMID: 39579520 DOI: 10.1016/j.smim.2024.101912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/18/2024] [Accepted: 11/18/2024] [Indexed: 11/25/2024]
Abstract
The complement system plays crucial roles in both innate and adaptive immune responses, facilitating the elimination of pathogens such as microorganisms and damaged cells, including cancer cells. It is tightly regulated and integrated with cell-mediated immunity. In the tumor microenvironment, the complement system performs both immune and nonimmune functions in tumor and immune cells through pathways that depend on or are independent of complement activation, thereby promoting immune evasion and tumor progression.
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Affiliation(s)
- Guijun Liu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Xuxiao He
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Gaoxiang Zhao
- Department of Oncology, Cancer Institute of The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266061, China
| | - Zhimin Lu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China.
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7
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Liu X, Chen L, Peng W, Deng H, Ni H, Tong H, Hu H, Wang S, Qian J, Liang A, Chen K. Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis. Front Immunol 2024; 15:1356869. [PMID: 38558800 PMCID: PMC10978743 DOI: 10.3389/fimmu.2024.1356869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.
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Affiliation(s)
- Xinyong Liu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Longwang Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Peng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongsheng Deng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongying Ni
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongjie Tong
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hangbo Hu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shengchao Wang
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jin Qian
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Andong Liang
- Nursing Faculty, School of Medicine, Jinhua Polytechnic, Jinhua, China
| | - Kun Chen
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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8
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Buelli S, Imberti B, Morigi M. The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation. Nephron Clin Pract 2024; 148:712-723. [PMID: 38452744 DOI: 10.1159/000538241] [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: 09/21/2023] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
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Affiliation(s)
- Simona Buelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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9
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Karhuvaara O, Vilén L, Nuutila J, Putus T, Atosuo J. Indoor microbial exposure increases complement component C3a and C-reactive protein concentrations in serum. Heliyon 2024; 10:e24104. [PMID: 38293363 PMCID: PMC10827445 DOI: 10.1016/j.heliyon.2024.e24104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 02/01/2024] Open
Abstract
Indoor exposure to microbial growth, caused by moisture damage, has been an established health risk for several decades. It is likely that a damp indoor environment contains biological pollutants that trigger both the innate and adaptive branches of the immune system. In this study, we investigated the association between moisture damage related microbial exposure and serum C3a, C5a and CRP concentrations in Finnish adults. Serum C3a and CRP concentrations were elevated in individuals exposed to moisture damage and microbial growth in an indoor air environment. The elevated concentrations may be due to environmental factors present in moisture-damaged buildings. Complement activation and the resulting proinflammatory cleavage products may be a driving factor in inflammatory responses following exposure to indoor moisture damage and related microbial growth.
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Affiliation(s)
- Outi Karhuvaara
- The Laboratory of Immunochemistry, Department of Biotechnology, Faculty of Science and Engineering, University of Turku, Turku, Finland
- Environmental Medicine and Occupational Health, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
| | - Liisa Vilén
- Environmental Medicine and Occupational Health, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
| | - Jari Nuutila
- The Laboratory of Immunochemistry, Department of Biotechnology, Faculty of Science and Engineering, University of Turku, Turku, Finland
| | - Tuula Putus
- Environmental Medicine and Occupational Health, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
| | - Janne Atosuo
- The Laboratory of Immunochemistry, Department of Biotechnology, Faculty of Science and Engineering, University of Turku, Turku, Finland
- Environmental Medicine and Occupational Health, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
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10
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Bode M, Herrnstadt GR, Dreher L, Ehnert N, Kirkerup P, Lindenmeyer MT, Meyer-Schwesinger CF, Ehmke H, Köhl J, Huber TB, Krebs CF, Steinmetz OM, Wiech T, Wenzel UO. Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage. Hypertension 2024; 81:138-150. [PMID: 37909169 DOI: 10.1161/hypertensionaha.123.21599] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/12/2023] [Indexed: 11/02/2023]
Abstract
BACKGROUND Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3+ (forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension. METHODS Data from the European Renal cDNA Bank, single cell sequencing and immunohistochemistry were examined in hypertensive patients. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in two models of Ang II (angiotensin II)-induced hypertension in knockout mice. RESULTS We found increased expression of C3aR, C5aR1 and Foxp3 cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. No differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation) or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned in C3aR-/- as well as C3aR/C5aR1-/- double knockout mice. The number of renal Tregs was not decreased in Ang II as well as in DOCA salt induced hypertension. CONCLUSIONS Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II-induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.
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Affiliation(s)
- Marlies Bode
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Georg R Herrnstadt
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Leonie Dreher
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
| | - Nicolas Ehnert
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
| | - Pia Kirkerup
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
| | - Maja T Lindenmeyer
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Catherine F Meyer-Schwesinger
- Department of Cellular and Integrative Physiology (C.M.-S., H.E.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Heimo Ehmke
- Department of Cellular and Integrative Physiology (C.M.-S., H.E.), University Hospital Hamburg-Eppendorf
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, Lübeck, Germany (J.K.)
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, OH (J.K.)
| | - Tobias B Huber
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Christian F Krebs
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Oliver M Steinmetz
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Thorsten Wiech
- Department of Pathology, Section of Nephropathology (T.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
| | - Ulrich O Wenzel
- III. Department of Medicine (M.B., G.R.H., L.D., N.E., P.K., M.T.L., T.B.H., C.F.K., O.M.S., U.O.W.), University Hospital Hamburg-Eppendorf
- Hamburg Center for Kidney Health (HCKH) (M.B., G.R.H., M.T.L., C.F.M.-S., T.B.H., C.F.K., O.M.S., T.W., U.O.W.)
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11
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Zou S, Jie H, Han X, Wang J. The role of neutrophil extracellular traps in sepsis and sepsis-related acute lung injury. Int Immunopharmacol 2023; 124:110436. [PMID: 37688916 DOI: 10.1016/j.intimp.2023.110436] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 09/11/2023]
Abstract
Neutrophils release neutrophil extracellular traps (NETs) to trap pathogenic microorganisms. NETs are involved in the inflammatory response and bacterial killing and clearance. However, their excessive activation can lead to an inflammatory storm in the body, which may damage tissues and cause organ dysfunction. Organ dysfunction is the main pathophysiological cause of sepsis and also a cause of the high mortality rate in sepsis. Acute lung injury caused by sepsis accounts for the highest proportion of organ damage in sepsis. NET formation can lead to the development of sepsis because by promoting the release of interleukin-1 beta, interleukin-8, and tumor necrosis factor-alpha, thereby accelerating acute lung injury. In this review, we describe the critical role of NETs in sepsis-associated acute lung injury and review the current knowledge and novel therapeutic approaches.
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Affiliation(s)
- Shujing Zou
- Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
| | - Hongyu Jie
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
| | - Xinai Han
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
| | - Jinghong Wang
- Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
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12
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Podestà MA, Chun N. Role of complement in humoral immunity. Curr Opin Organ Transplant 2023; 28:327-332. [PMID: 37582054 PMCID: PMC10530608 DOI: 10.1097/mot.0000000000001095] [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] [Indexed: 08/17/2023]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection (AMR) after solid organ transplantation remains an unsolved problem and leads to poor early and late patient outcomes. The complement system is a well recognized pathogenic mediator of AMR. Herein, we review the known molecular mechanisms of disease and results from ongoing clinical testing of complement inhibitors after solid organ transplant. RECENT FINDINGS Activation and regulation of the complement cascade is critical not only for the terminal effector function of donor-specific antibodies, but also for the regulation of T and B cell subsets to generate the antidonor humoral response. Donor-specific antibodies (DSA) have heterogenous features, as are their interactions with the complement system. Clinical testing of complement inhibitors in transplant patients have shown good safety profiles but mixed efficacy to date. SUMMARY The complement cascade is a critical mediator of AMR and clinical trials have shown early promising results. With the steady emergence of novel complement inhibitors and our greater understanding of the molecular mechanisms linking complement and AMR, there is greater optimism now for new prognostic and therapeutic tools to deploy in transplant patients with AMR.
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Affiliation(s)
- Manuel Alfredo Podestà
- Renal Division, Department of Medicine, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Nicholas Chun
- Translational Transplant Research Center and Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, NY
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13
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Laumonnier Y, Korkmaz RÜ, Nowacka AA, Köhl J. Complement-mediated immune mechanisms in allergy. Eur J Immunol 2023; 53:e2249979. [PMID: 37381711 DOI: 10.1002/eji.202249979] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 06/30/2023]
Abstract
Allergic conditions are associated with canonical and noncanonical activation of the complement system leading to the release of several bioactive mediators with inflammatory and immunoregulatory properties that regulate the immune response in response to allergens during the sensitization and/or the effector phase of allergic diseases. Further, immune sensors of complement and regulator proteins of the cascade impact on the development of allergies. These bioactive mediators comprise the small and large cleavage fragments of C3 and C5. Here, we provide an update on the multiple roles of immune sensors, regulators, and bioactive mediators of complement in allergic airway diseases, food allergies, and anaphylaxis. A particular emphasis is on the anaphylatoxins C3a and C5a and their receptors, which are expressed on many of the effector cells in allergy such as mast cells, eosinophils, basophils, macrophages, and neutrophils. Also, we will discuss the multiple pathways, by which the anaphylatoxins initiate and control the development of maladaptive type 2 immunity including their impact on innate lymphoid cell recruitment and activation. Finally, we briefly comment on the potential to therapeutically target the complement system in different allergic conditions.
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Affiliation(s)
- Yves Laumonnier
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- Institute for Nutritional Medicine, University of Lübeck, Lübeck, Germany
- Airway Research Center North, Member of the German Center for Lung Research (DZL), Lübeck, Germany
| | - Rabia Ülkü Korkmaz
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Alicja A Nowacka
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- Airway Research Center North, Member of the German Center for Lung Research (DZL), Lübeck, Germany
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, USA
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14
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Zhang C, Cao K, Yang M, Wang Y, He M, Lu J, Huang Y, Zhang G, Liu H. C5aR1 blockade reshapes immunosuppressive tumor microenvironment and synergizes with immune checkpoint blockade therapy in high-grade serous ovarian cancer. Oncoimmunology 2023; 12:2261242. [PMID: 37791232 PMCID: PMC10543342 DOI: 10.1080/2162402x.2023.2261242] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/15/2023] [Indexed: 10/05/2023] Open
Abstract
High-grade serous ovarian cancer (HGSC), with a modest response to immune checkpoint blockade (ICB) targeting PD-1/PD-L1 monotherapy, is densely infiltrated by M2-polarized tumor-associated macrophages (TAMs) and regulatory T (Treg) cells. The complement C5a/C5aR1 axis contributes to the programming of the immunosuppressive phenotype of TAMs in solid tumors and represents a promising immunomodulatory target for treating HGSCs. Here, we aimed to identify the relevance of C5aR1 in prognosis, immune microenvironment, and immunotherapy response in HGSCs. The expression and relationship of C5aR1 with tumor-infiltrating immune cells were assessed by immunohistochemistry and flow cytometry in the training cohort (n = 120) and fresh HGSC tissues (n = 36). Transcriptomic analyses of the xenografts delineated the mechanisms driving the immunomodulatory activity of PMX53, an orally bioavailable C5aR1 inhibitor. Therapeutic relevance was confirmed in ex vivo tumor cultures and The Cancer Genome Atlas (TCGA) datasets. C5aR1 expression independently predicted dismal prognosis and was linked to the immunoevasive subtype of HGSC, characterized by increased infiltration of pro-tumor cells (Treg cells, M2-polarized macrophages, and neutrophils) and impaired CD8+T functions. PMX53 antagonized subcutaneous tumor growth, modulated immunosuppressive mechanisms and synergized with aPD-1 in several tumor types. Single-cell RNA-seq analysis revealed predominant C5aR1 expression in TAMs, with an immunosuppressive-related expression signature in C5aR1+TAMs. Furthermore, the combination of C5aR1 and PD-L1 was associated with specific molecular characteristics and matched clinical response annotations. Therefore, the abundance of C5aR1 could predict an inferior prognosis in HGSCs, and incorporating PD-L1 may serve as a novel predictive biomarker to guide therapeutic options.
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Affiliation(s)
- Chen Zhang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Kankan Cao
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Moran Yang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Yiying Wang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Mengdi He
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Jiaqi Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Yan Huang
- Department of Gynecologic Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Guodong Zhang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Haiou Liu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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15
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Gramkow AM, Isaksson GL, Palarasah Y, Jensen BL, Alnor A, Thiesson HC. Exploration of complement split products in plasma and urine as biomarkers of kidney graft rejection. Immunobiology 2023; 228:152462. [PMID: 37406469 DOI: 10.1016/j.imbio.2023.152462] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/13/2023] [Accepted: 06/22/2023] [Indexed: 07/07/2023]
Abstract
INTRODUCTION The complement system, consisting of more than thirty different soluble and cell-bound proteins, exerts essential functions both in the innate and adaptive immune systems and is believed to be an important contributor to allograft injury in kidney transplantation. The anaphylatoxins C3a and C5a are powerful chemoattractants, recruiting immune effector cells toward the site of complement activation and enhance T-cell response, while C3dg binding to CR2 on B-cells, enhances B-cell immunity at several stages of the B-cell differentiation. Complement split products in plasma and urine could reflect ongoing inflammation and tissue injury. We, therefore, investigated if complement split products increase in plasma and urine in kidney transplant recipients with rejection. METHOD In this case-control feasibility study, complement factors C3a, C3dg, C4a, and C5a were measured in plasma and C3dg and sC5b-9 associated C9 neoantigen in urine in 15 kidney transplant recipients with rejection (cases) and 15 kidney transplant recipients without (controls). The groups were matched on the type of transplantation and the time from transplantation to sampling. The complement split products were compared (i) between cases and controls and (ii) within the rejection group over time, comparing the measurements at rejection with measurements where the kidney transplant recipients were clinically stable. Possible moderators were explored, and results adjusted accordingly. P values < 0.05 were considered significant. Plasma C3dg was analyzed by immune-electrophoresis, plasma C3a, plasma C4a, and plasma C5a by flow cytometry, and urine C3dg and urine C9neo by ELISA. RESULTS In plasma, there were no significant differences between the rejection and the control group. However, steroids and pretransplant C3dg levels significantly influenced C3dg. Within the rejection group, plasma C3a and C3dg were significantly higher at the time of rejection compared to the stable phase (p < 0.01). In urine, C3dg/creatinine and C9 neoantigen/creatinine ratios were not different between the rejection and the control group. Urine C3dg/creatinine and urine C9 neoantigen/creatinine ratios correlated to urine albumin and significantly increased after the transplantation (p < 0.001). CONCLUSION This study shows increased plasma C3a and C3dg in kidney transplant recipients, primarily with T cell mediated rejection. This finding suggests that consecutive measurements of C3a and C3dg in plasma could be applicable to monitor alloreactivity in kidney transplant recipients. Urine complement split products are unsuitable as rejection biomarkers since the permeability of the glomerular filtration barrier strongly influences them. Prospective longitudinal studies on plasma C3a and C3dg dynamics will be needed to validate present findings.
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Affiliation(s)
- Ann-Maria Gramkow
- Dept. of Nephrology, Odense University Hospital, Kløvervænget 6, 5000 Odense, Denmark; Dept. of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense, Denmark.
| | - Gustaf L Isaksson
- Dept. of Nephrology, Odense University Hospital, Kløvervænget 6, 5000 Odense, Denmark; Dept. of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense, Denmark.
| | - Yaseelan Palarasah
- Dept. of Molecular Medicine, Cancer and Inflammation, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense, Denmark.
| | - Boye L Jensen
- Dept. of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense, Denmark.
| | - Anne Alnor
- Dept. of Clinical Immunology and Biochemistry, Hospital Lillebælt, Beridderbakken 4, 7100 Vejle, Denmark; Dept. of Clinical Biochemistry, Odense University Hospital, J.B. Winsløwsvej 4, 5000 Odense, Denmark.
| | - Helle C Thiesson
- Dept. of Nephrology, Odense University Hospital, Kløvervænget 6, 5000 Odense, Denmark; Dept. of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense, Denmark.
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16
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Gibson B, Connelly C, Moldakhmetova S, Sheerin NS. Complement activation and kidney transplantation; a complex relationship. Immunobiology 2023; 228:152396. [PMID: 37276614 DOI: 10.1016/j.imbio.2023.152396] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/07/2023]
Abstract
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
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Affiliation(s)
- B Gibson
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - C Connelly
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - S Moldakhmetova
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - N S Sheerin
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK.
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17
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Short S, Lewik G, Issa F. Research Highlights. Transplantation 2023; 107:797-798. [PMID: 37779390 DOI: 10.1097/tp.0000000000004605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Affiliation(s)
- Sarah Short
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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18
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Kong LR, Chen XH, Sun Q, Zhang KY, Xu L, Ding L, Zhou YP, Zhang ZB, Lin JR, Gao PJ. Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway. Cell Rep 2023; 42:112078. [PMID: 36735535 DOI: 10.1016/j.celrep.2023.112078] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/29/2022] [Accepted: 01/23/2023] [Indexed: 02/04/2023] Open
Abstract
Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.
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Affiliation(s)
- Ling-Ran Kong
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Hui Chen
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qing Sun
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai-Yuan Zhang
- Department of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lian Xu
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liliqiang Ding
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan-Ping Zhou
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ze-Bei Zhang
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing-Rong Lin
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping-Jin Gao
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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19
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Washburn RL, Dufour JM. Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response. Int J Mol Sci 2023; 24:ijms24043371. [PMID: 36834786 PMCID: PMC9965741 DOI: 10.3390/ijms24043371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Sertoli cells within the testis are instrumental in providing an environment for spermatogenesis and protecting the developing germ cells from detrimental immune responses which could affect fertility. Though these immune responses consist of many immune processes, this review focuses on the understudied complement system. Complement consists of 50+ proteins including regulatory proteins, immune receptors, and a cascade of proteolytic cleavages resulting in target cell destruction. In the testis, Sertoli cells protect the germ cells from autoimmune destruction by creating an immunoregulatory environment. Most studies on Sertoli cells and complement have been conducted in transplantation models, which are effective in studying immune regulation during robust rejection responses. In grafts, Sertoli cells survive activated complement, have decreased deposition of complement fragments, and express many complement inhibitors. Moreover, the grafts have delayed infiltration of immune cells and contain increased infiltration of immunosuppressive regulatory T cells as compared to rejecting grafts. Additionally, anti-sperm antibodies and lymphocyte infiltration have been detected in up to 50% and 30% of infertile testes, respectively. This review seeks to provide an updated overview of the complement system, describe its relationship with immune cells, and explain how Sertoli cells may regulate complement in immunoprotection. Identifying the mechanism Sertoli cells use to protect themselves and germ cells against complement and immune destruction is relevant for male reproduction, autoimmunity, and transplantation.
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Affiliation(s)
- Rachel L Washburn
- Immunology and Infectious Diseases, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Jannette M Dufour
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
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20
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Peng Q, Nowocin A, Ratnasothy K, Smith RA, Smyth LA, Lechler RI, Dorling A, Lombardi G. Inhibition of thrombin on endothelium enhances recruitment of regulatory T cells during IRI and when combined with adoptive Treg transfer, significantly protects against acute tissue injury and prolongs allograft survival. Front Immunol 2023; 13:980462. [PMID: 36793549 PMCID: PMC9924086 DOI: 10.3389/fimmu.2022.980462] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/28/2022] [Indexed: 01/31/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) amplifies T cell alloimmune responses after transplantation with thrombin playing a key pro-inflammatory role. To explore the influence of thrombin on regulatory T cell recruitment and efficacy we used a well-established model of IRI in the native murine kidney. Administration of the cytotopic thrombin inhibitor PTL060 inhibited IRI, and by skewing expression of chemokines (reducing CCL2 and CCL3 but increasing CCL17 and CCL22) increased the infiltration of M2 macrophages and Tregs. When PTL060 was combined with infusion of additional Tregs, these effects were further amplified. To test the benefits of thrombin inhibition in a transplant model, BALB/c hearts were transplanted into B6 mice with or without perfusion with PTL060 in combination with Tregs. Thrombin inhibition or Treg infusion alone led to small increments in allograft survival. However, the combined therapy led to modest graft prolongation by the same mechanisms as in renal IRI; graft survival was accompanied by increased numbers of Tregs and anti-inflammatory macrophages, and reduced expression of pro-inflammatory cytokines. While the grafts succumbed to rejection associated with the emergence of alloantibody, these data suggest that thrombin inhibition within the transplant vasculature enhances the efficacy of Treg infusion, a therapy that is currently entering the clinic to promote transplant tolerance.
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Affiliation(s)
- Qi Peng
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Anna Nowocin
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Kulachelvy Ratnasothy
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Richard A. Smith
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Lesley A. Smyth
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom,School of Health, Sport and Bioscience, University of East London, London, United Kingdom
| | - Robert I. Lechler
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Anthony Dorling
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Giovanna Lombardi
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom,*Correspondence: Giovanna Lombardi,
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21
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Washburn RL, Martinez-Marin D, Korać K, Sniegowski T, Rodriguez AR, Chilton BS, Hibler T, Pruitt K, Bhutia YD, Dufour JM. The Sertoli Cell Complement Signature: A Suspected Mechanism in Xenograft Survival. Int J Mol Sci 2023; 24:ijms24031890. [PMID: 36768217 PMCID: PMC9916409 DOI: 10.3390/ijms24031890] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across immunological barriers; thus, understanding the mechanisms behind this unique survival would be of great benefit to the transplantation field. This study focused on Sertoli cell inhibition of complement as relevant in xenotransplantation. Neonatal pig Sertoli cells (NPSCs) survived activated human complement in vitro while neonatal pig islet (NPI) aggregates and pig aortic endothelial cell (PAEC) survival were diminished to about 65% and 12%, respectively. PAECs cultured in NPSC-conditioned media and human complement demonstrated a 200% increase in survival suggesting that NPSCs secrete complement-inhibiting substances that confer protection. Bioinformatic and molecular analyses identified 21 complement inhibitors expressed by NPSCs with several significantly increased in NPSCs compared to NPIs or PAECs. Lastly, RNA sequencing revealed that NPSCs express 25 other complement factors including cascade components and receptors. Overall, this study identified the most comprehensive Sertoli cell complement signature to date and indicates that the expression of a variety of complement inhibitors ensures a proper regulation of complement through redundant inhibition points. Understanding the regulation of the complement system should be further investigated for extending xenograft viability.
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Affiliation(s)
- Rachel L. Washburn
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79404, USA
| | - Dalia Martinez-Marin
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79404, USA
| | - Ksenija Korać
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Tyler Sniegowski
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Alexis R. Rodriguez
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Beverly S. Chilton
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Taylor Hibler
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79404, USA
| | - Kevin Pruitt
- Department of Immunology and Molecular Microbiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79404, USA
| | - Yangzom D. Bhutia
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
| | - Jannette M. Dufour
- Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79424, USA
- Correspondence:
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22
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Farshbafnadi M, Razi S, Rezaei N. Transplantation. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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23
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Cumpelik A, Cody E, Yu SMW, Grasset EK, Dominguez-Sola D, Cerutti A, Heeger PS. Cutting Edge: Neutrophil Complement Receptor Signaling Is Required for BAFF-Dependent Humoral Responses in Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:19-23. [PMID: 36454023 PMCID: PMC9780177 DOI: 10.4049/jimmunol.2200410] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 11/06/2022] [Indexed: 12/24/2022]
Abstract
T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, but mechanisms effectively linking neutrophil activation to TI B cell responses are incompletely understood. Using germline and conditional knockout mice, we found that TI humoral responses involve alternative pathway complement activation and neutrophil-expressed C3a and C5a receptors (C3aR1/C5aR1) that promote BAFF-dependent B1 cell expansion and TI Ab production. Conditional absence of C3aR1/C5aR1 on neutrophils lowered serum BAFF levels, led to fewer Peyer's patch germinal center B cells, reduced germinal center B cells IgA class-switching, and lowered fecal IgA levels. Together, the results indicate that sequential activation of complement on neutrophils crucially supports humoral TI and mucosal IgA responses through upregulating neutrophil production of BAFF.
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Affiliation(s)
- Arun Cumpelik
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Evan Cody
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Samuel Mon-Wei Yu
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Emilie K Grasset
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - David Dominguez-Sola
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Andrea Cerutti
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Peter S Heeger
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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24
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Navaneethabalakrishnan S, Smith HL, Arenaz CM, Goodlett BL, McDermott JG, Mitchell BM. Update on Immune Mechanisms in Hypertension. Am J Hypertens 2022; 35:842-851. [PMID: 35704473 PMCID: PMC9527774 DOI: 10.1093/ajh/hpac077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 02/02/2023] Open
Abstract
The contribution of immune cells in the initiation and maintenance of hypertension is undeniable. Several studies have established the association between hypertension, inflammation, and immune cells from the innate and adaptive immune systems. Here, we provide an update to our 2017 American Journal of Hypertension review on the overview of the cellular immune responses involved in hypertension. Further, we discuss the activation of immune cells and their contribution to the pathogenesis of hypertension in different in vivo models. We also highlight existing gaps in the field of hypertension that need attention. The main goal of this review is to provide a knowledge base for translational research to develop therapeutic strategies that can improve cardiovascular health in humans.
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Affiliation(s)
| | - Hannah L Smith
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, Texas, USA
| | - Cristina M Arenaz
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, Texas, USA
| | - Bethany L Goodlett
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, Texas, USA
| | - Justin G McDermott
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, Texas, USA
| | - Brett M Mitchell
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, Texas, USA
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25
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Duneton C, Winterberg PD, Ford ML. Activation and regulation of alloreactive T cell immunity in solid organ transplantation. Nat Rev Nephrol 2022; 18:663-676. [PMID: 35902775 PMCID: PMC9968399 DOI: 10.1038/s41581-022-00600-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 01/18/2023]
Abstract
Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens - through direct, indirect or semi-direct pathways - will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance.
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Affiliation(s)
- Charlotte Duneton
- Paediatric Nephrology, Robert Debré Hospital, Paris, France
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Pamela D Winterberg
- Paediatric Nephrology, Emory University Department of Paediatrics and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Mandy L Ford
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
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26
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Smith CJ, Ross N, Kamal A, Kim KY, Kropf E, Deschatelets P, Francois C, Quinn WJ, Singh I, Majowicz A, Mingozzi F, Kuranda K. Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood. Front Immunol 2022; 13:999021. [PMID: 36189251 PMCID: PMC9523746 DOI: 10.3389/fimmu.2022.999021] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses a significant challenge for the durability and safety of AAV-mediated gene therapy. Here, we characterize the innate immune response to AAV in human whole blood. We identified neutrophils, monocyte-related dendritic cells, and monocytes as the most prevalent cell subsets able to internalize AAV particles, while conventional dendritic cells were the most activated in terms of the CD86 co-stimulatory molecule upregulation. Although low titers (≤1:10) of AAV neutralizing antibodies (NAb) in blood did not have profound effects on the innate immune response to AAV, higher NAb titers (≥1:100) significantly increased pro-inflammatory cytokine/chemokine secretion, vector uptake by antigen presenting cells (APCs) and complement activation. Interestingly, both full and empty viral particles were equally potent in inducing complement activation and cytokine secretion. By using a compstatin-based C3 and C3b inhibitor, APL-9, we demonstrated that complement pathway inhibition lowered CD86 levels on APCs, AAV uptake, and cytokine/chemokine secretion in response to AAV. Together these results suggest that the pre-existing humoral immunity to AAV may contribute to trigger adverse immune responses observed in AAV-based gene therapy, and that blockade of complement pathway may warrant further investigation as a potential strategy for decreasing immunogenicity of AAV-based therapeutics.
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Affiliation(s)
- Corinne J. Smith
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Nikki Ross
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Ali Kamal
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Kevin Y. Kim
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Elizabeth Kropf
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | | | - Cedric Francois
- Research Department, Apellis Pharmaceuticals, Waltham, MA, United States
| | - William J. Quinn
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Inderpal Singh
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Anna Majowicz
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Federico Mingozzi
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
| | - Klaudia Kuranda
- Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United States
- *Correspondence: Klaudia Kuranda,
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27
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Gao S, Cui Z, Zhao MH. Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy. J Am Soc Nephrol 2022; 33:1742-1756. [PMID: 35777783 PMCID: PMC9529185 DOI: 10.1681/asn.2021101384] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/09/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic implications. This study investigated the role of C3a and the C3a receptor (C3aR) in the pathogenesis of MN. METHODS C3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma +/- C3aR blockade (SB290157, JR14a). C3aR antagonists were administered to rats with Heymann nephritis on day 0 or after proteinuria. Clinical and pathologic parameters, specific IgG and complement activation, and podocyte injuries were then assessed. RESULTS In the glomeruli, C3aR staining merged well with podocin. Overexpression of C3aR correlated positively with proteinuria, serum creatinine, and no response to treatments. Human podocytes exposed to MN plasma showed increased expression of PLA2R, C3aR, and Wnt3/β-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonists could block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. The increased plasma C3a levels and overexpression of C3aR were also alleviated. Specific, but not total, IgG levels decreased, with less deposition of rat IgG in glomeruli and subsequent reduction of C1q, factor B, and C5b-9. CONCLUSION C3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.
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Affiliation(s)
- Shuang Gao
- Renal Division, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Ming-hui Zhao
- Renal Division, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
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28
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Schanzenbacher J, Köhl J, Karsten CM. Anaphylatoxins spark the flame in early autoimmunity. Front Immunol 2022; 13:958392. [PMID: 35958588 PMCID: PMC9358992 DOI: 10.3389/fimmu.2022.958392] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors via dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.
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Affiliation(s)
- Jovan Schanzenbacher
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- Division of Immunobiology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Christian M. Karsten
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- *Correspondence: Christian M. Karsten,
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29
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Țiburcă L, Bembea M, Zaha DC, Jurca AD, Vesa CM, Rațiu IA, Jurca CM. The Treatment with Interleukin 17 Inhibitors and Immune-Mediated Inflammatory Diseases. Curr Issues Mol Biol 2022; 44:1851-1866. [PMID: 35678656 PMCID: PMC9164043 DOI: 10.3390/cimb44050127] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/23/2022] [Accepted: 04/24/2022] [Indexed: 12/29/2022] Open
Abstract
IL-17 inhibitors (IL-17i) are medicines used to treat dermatological and rheumatic diseases They belong to a class of medicines called biological disease-modifying anti-rheumatic drugs (bDMARDs). This class of drugs has had a major impact on the therapy of autoimmune diseases, being much safer and more effective than treatment with small molecules. At the same time, they have highly beneficial effects on skin and joint changes, and their efficacy has been extensively monitored and demonstrated in numerous clinical trials. More and more such drugs are still being discovered today to ensure the best possible treatment of these patients, but more frequently and relatively constantly three agents are used. Two of them (Secukinumab and Ixekizumab) inhibit IL-17A directly, and the third, Brodamulab, inhibits the IL-17A receptor. Although they are extremely effective in the treatment of these diseases, sometimes their administration has been associated with paradoxical effects, i.e., there is an exacerbation of the inflammatory process. Tough, clinical trials of IL-17i have described cases of exacerbation or even onset of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, after administration of these drugs in patients previously diagnosed with psoriasis (PS), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). The pathophysiological mechanism of action is not well understood at present. One explanation would be that this hyperreactive inflammatory process would be triggered by Interferon 1 derived from dendritic plasma cells. Even though there are many reports in the recent literature about the role of IL17i in the onset of IBD, conclusions of studies do not converge. Some of them show an increased incidence of IBD in patients treated with IL17i, while some others affirm their safety of them. In the near future we will surely have more data emerging from ongoing meta-analyses regarding safety of use IL17i in patients who are at risk of developing IBD. Clinical and paraclinical evaluation (inflammatory intestinal markers) are carefully advised before recommending treatment with IL-17i and after initiation of treatment, and prospective surveillance by clinical and biomarkers of patients treated with IL-17i is absolutely essential to capture the onset of IBD.
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Affiliation(s)
- Laura Țiburcă
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
| | - Marius Bembea
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
| | - Dana Carmen Zaha
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Alexandru Daniel Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Cosmin Mihai Vesa
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Ioana Adela Rațiu
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Claudia Maria Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
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30
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Toyama C, Maeda A, Kogata S, Takase K, Kodama T, Masahata K, Ueno T, Kamiyama M, Tazuke Y, Eguchi H, Matsunami K, Miyagawa S, Okuyama H. Effect of a C5a receptor antagonist on macrophage function in an intestinal transplant rat model. Transpl Immunol 2022; 72:101559. [DOI: 10.1016/j.trim.2022.101559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 11/24/2022]
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Freiwald T, Afzali B. Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Adv Immunol 2021; 152:1-81. [PMID: 34844708 PMCID: PMC8905641 DOI: 10.1016/bs.ai.2021.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
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Affiliation(s)
- Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, United States; Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Behdad Afzali
- Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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32
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A study of the mechanisms responsible for the action of new immunosuppressants and their effects on rat small intestinal transplantation. Transpl Immunol 2021; 70:101497. [PMID: 34785307 DOI: 10.1016/j.trim.2021.101497] [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: 08/19/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 11/20/2022]
Abstract
In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.
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33
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Scott J, Ruchaud-Sparagano MH, Musgrave K, Roy AI, Wright SE, Perry JD, Conway Morris A, Rostron AJ, Simpson AJ. Phosphoinositide 3-Kinase δ Inhibition Improves Neutrophil Bacterial Killing in Critically Ill Patients at High Risk of Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:1776-1784. [PMID: 34497151 DOI: 10.4049/jimmunol.2000603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/20/2021] [Indexed: 11/19/2022]
Abstract
Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care unit-acquired infection. PI3Kδ is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3Kδ inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3Kδ, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3Kδ inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3Kδ inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit-acquired infection. PI3Kδ activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3Kδ inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3Kδ inhibitors warrants investigation in this setting.
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Affiliation(s)
- Jonathan Scott
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Marie-Hélène Ruchaud-Sparagano
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kathryn Musgrave
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Alistair I Roy
- Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, United Kingdom
| | - Stephen E Wright
- Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - John D Perry
- Microbiology Department, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; and
| | - Andrew Conway Morris
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Anthony J Rostron
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, United Kingdom
| | - A John Simpson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;
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Shiek SS, Mani MS, Kabekkodu SP, Dsouza HS. Health repercussions of environmental exposure to lead: Methylation perspective. Toxicology 2021; 461:152927. [PMID: 34492314 DOI: 10.1016/j.tox.2021.152927] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/23/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022]
Abstract
Lead (Pb) exposure has been a major public health concern for a long time now due to its permanent adverse effects on the human body. The process of lead toxicity has still not been fully understood, but recent advances in Omics technology have enabled researchers to evaluate lead-mediated alterations at the epigenome-wide level. DNA methylation is one of the widely studied and well-understood epigenetic modifications. Pb has demonstrated its ability to induce not just acute deleterious health consequences but also alters the epi-genome such that the disease manifestation happens much later in life as supported by Barkers Hypothesis of the developmental origin of health and diseases. Furthermore, these alterations are passed on to the next generation. Based on previous in-vivo, in-vitro, and human studies, this review provides an insight into the role of Pb in the development of several human disorders.
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Affiliation(s)
- Sadiya Sadiq Shiek
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Monica Shirley Mani
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| | - Herman S Dsouza
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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35
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Li Y, Yi JS, Howard JF, Chopra M, Russo MA, Guptill JT. Cellular changes in eculizumab early responders with generalized myasthenia gravis. Clin Immunol 2021; 231:108830. [PMID: 34450290 DOI: 10.1016/j.clim.2021.108830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 11/19/2022]
Abstract
Eculizumab (ECU), a C5 complement inhibitor, is approved to treat acetylcholine receptor autoantibody positive generalized myasthenia gravis (AChR MG). The clinical effect of ECU relies on inhibition of the terminal complement complex; however, the effect of ECU on lymphocytes is largely unknown. We evaluated innate and adaptive immunity among AChR MG patients (N = 3) before ECU and ≥3 months later while on stable therapy, and found reduced activation markers in memory CD4+ T cell subsets, increased regulatory T cell populations, and reduced frequencies of CXCR5+HLA-DR+CCR7+ Tfh subsets and CD11b+ migratory memory B cells. We observed increases within CD8+ T cell subsets that were terminally differentiated and senescent. Our data suggest complement inhibition with ECU modulates the adaptive immunity in patients with MG, consistent with preclinical data showing changes in complement-mediated signaling by T- and antigen-presenting cells. These findings extend our understanding of ECU's mechanism of action when treating patients with MG.
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Affiliation(s)
- Yingkai Li
- Department of Neurology, Duke University Medical Center, Durham, NC, USA
| | - John S Yi
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - James F Howard
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Manisha Chopra
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Melissa A Russo
- Department of Neurology, Duke University Medical Center, Durham, NC, USA
| | - Jeffrey T Guptill
- Department of Neurology, Duke University Medical Center, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA.
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Han J, Zhang X. Complement Component C3: A Novel Biomarker Participating in the Pathogenesis of Non-alcoholic Fatty Liver Disease. Front Med (Lausanne) 2021; 8:653293. [PMID: 34395461 PMCID: PMC8358116 DOI: 10.3389/fmed.2021.653293] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disorder worldwide. The pathological spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) that induces progressive liver cirrhosis and eventually hepatocellular carcinoma (HCC). However, the molecular mechanisms driving the transformation of NASH are obscure. There is a compelling need for understanding the pathogenic mechanisms of NASH, and thereby providing new insight into mechanism-based therapy. Currently, several studies reported that complement system, an innate immune system, played an important role in the pathogenesis of NAFLD, which was also proved by our recent study. Complement component 3 (C3), a protein of the innate immune system, plays a hub role in the complement system. Herein, we present a review on the role and molecular mechanism of C3 in NASH as well as its implication in NASH diagnosis and treatment.
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Affiliation(s)
- Juqiang Han
- Institute of Liver Disease, The 7th Medical Centre of Chinese People Liberation Army General Hospital, Beijing, China.,The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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Senent Y, Ajona D, González-Martín A, Pio R, Tavira B. The Complement System in Ovarian Cancer: An Underexplored Old Path. Cancers (Basel) 2021; 13:3806. [PMID: 34359708 PMCID: PMC8345190 DOI: 10.3390/cancers13153806] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest results in ovarian cancer. Emerging evidence underscores the relevance of the components of innate and adaptive immunity in ovarian cancer progression and response to treatment. Particularly, over the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator of the tumor microenvironment in cancer immunity. Tumor-associated complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in different clinical contexts is still poorly understood. Detailed knowledge of the interplay between ovarian cancer cells and complement is required to develop new immunotherapy combinations and biomarkers. In this context, we discuss the possibility of targeting complement to overcome some of the hurdles encountered in the treatment of ovarian cancer.
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Affiliation(s)
- Yaiza Senent
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
| | - Daniel Ajona
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Antonio González-Martín
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain
| | - Ruben Pio
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Beatriz Tavira
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain
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Fan Y, Wang Y, Yu S, Chang J, Yan Y, Wang Y, Bian Y. Natural products provide a new perspective for anti-complement treatment of severe COVID-19: a review. Chin Med 2021; 16:67. [PMID: 34321065 PMCID: PMC8318062 DOI: 10.1186/s13020-021-00478-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/21/2021] [Indexed: 01/08/2023] Open
Abstract
Exaggerated immune response and cytokine storm are accounted for the severity of COVID-19, including organ dysfunction, especially progressive respiratory failure and generalized coagulopathy. Uncontrolled activation of complement contributes to acute and chronic inflammation, the generation of cytokine storm, intravascular coagulation and cell/tissue damage, which may be a favorable target for the treatment of multiple organ failure and reduction of mortality in critically ill patients with COVID-19. Cytokine storm suppression therapy can alleviate the symptoms of critically ill patients to some extent, but as a remedial etiological measure, its long-term efficacy is still questionable. Anti-complement therapy has undoubtedly become an important hotspot in the upstream regulation of cytokine storm. However, chemosynthetic complement inhibitors are expensive, and their drug resistance and long-term side effects require further investigation. New complement inhibitors with high efficiency and low toxicity can be obtained from natural products at low development cost. This paper puts forward some insights of the development of natural anti-complement products in traditional Chinese medicine, that may provide a bright perspective for suppressing cytokine storm in critically ill patients with COVID-19.
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Affiliation(s)
- Yadong Fan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China
| | - Ying Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China
| | - Shuang Yu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China
| | - Jun Chang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China
| | - Yiqi Yan
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yiyang Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China
| | - Yuhong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No.10 PoYangHu Road, JingHai, District, Tianjin, 301617, People's Republic of China.
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Wenzel UO, Kemper C, Bode M. The role of complement in arterial hypertension and hypertensive end organ damage. Br J Pharmacol 2021; 178:2849-2862. [PMID: 32585035 PMCID: PMC10725187 DOI: 10.1111/bph.15171] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/23/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022] Open
Abstract
Increasing evidence indicates that hypertension and hypertensive end organ damage are not only mediated by haemodynamic injury but that inflammation also plays an important role. The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells. As an important effector arm of innate immunity, it plays also central roles in the regulation of adaptive immunity. Thus, complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on the vasculature. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical haemolytic uraemic syndrome suggest also a role for complement in the development of malignant nephrosclerosis. Here, we review the role of complement in hypertension and hypertensive end organ damage. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Ulrich O Wenzel
- III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Marlies Bode
- III. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
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40
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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: 38] [Impact Index Per Article: 9.5] [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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O’Brien RM, Cannon A, Reynolds JV, Lysaght J, Lynam-Lennon N. Complement in Tumourigenesis and the Response to Cancer Therapy. Cancers (Basel) 2021; 13:1209. [PMID: 33802004 PMCID: PMC7998562 DOI: 10.3390/cancers13061209] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/16/2022] Open
Abstract
In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.
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Affiliation(s)
- Rebecca M. O’Brien
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Aoife Cannon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - John V. Reynolds
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - Joanne Lysaght
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
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Gadwa J, Bickett TE, Darragh LB, Knitz MW, Bhatia S, Piper M, Van Court B, Bhuvane S, Nguyen D, Nangia V, Kleczko EK, Nemenoff RA, Karam SD. Complement C3a and C5a receptor blockade modulates regulatory T cell conversion in head and neck cancer. J Immunother Cancer 2021; 9:e002585. [PMID: 33789881 PMCID: PMC8016081 DOI: 10.1136/jitc-2021-002585] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Resistance to therapy is a major problem in treating head and neck squamous cell carcinomas (HNSCC). Complement system inhibition has been shown to reduce tumor growth, metastasis, and therapeutic resistance in other tumor models, but has yet to be explored in the context of HNSCC. Here, we tested the effects of complement inhibition and its therapeutic potential in HNSCC. METHODS We conducted our studies using two Human Papilloma Virus (HPV)-negative HNSCC orthotopic mouse models. Complement C3aR and C5aR1 receptor antagonists were paired with radiation therapy (RT). Tumor growth was measured and immune populations from tumor, lymph node, and peripheral blood were compared among various treatment groups. Genetically engineered mouse models DEREG and C3-/- were used in addition to standard wild type models. Flow cytometry, clinical gene sets, and in vitro assays were used to evaluate the role complement receptor blockade has on the immunological makeup of the tumor microenvironment. RESULTS In contrast to established literature, inhibition of complement C3a and C5a signaling using receptor antagonists accelerated tumor growth in multiple HNSCC cell lines and corresponded with increased frequency of regulatory T cell (Treg) populations. Local C3a and C5a signaling has importance for CD4 T cell homeostasis and eventual development into effector phenotypes. Interruption of this signaling axis drives a phenotypic conversion of CD4+ T cells into Tregs, characterized by enhanced expression of Foxp3. Depletion of Tregs reversed tumor growth, and combination of Treg depletion and C3a and C5a receptor inhibition decreased tumor growth below that of the control groups. Complete knockout of C3 does not harbor the expected effect on tumor growth, indicating a still undetermined compensatory mechanism. Dexamethasone is frequently prescribed to patients undergoing RT and inhibits complement activation. We report no deleterious effects associated with dexamethasone due to complement inhibition. CONCLUSIONS Our data establish Tregs as a pro-tumorigenic driver during complement inhibition and provide evidence that targeted C3a and C5a receptor inhibition may add therapeutic advantage when coupled with anti-Treg therapy.
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MESH Headings
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Complement C3/genetics
- Complement C3/metabolism
- Complement Inactivating Agents/toxicity
- Dexamethasone/toxicity
- Forkhead Transcription Factors/metabolism
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/immunology
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/pathology
- Humans
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Receptor, Anaphylatoxin C5a/antagonists & inhibitors
- Receptor, Anaphylatoxin C5a/metabolism
- Receptors, Complement/antagonists & inhibitors
- Receptors, Complement/metabolism
- Signal Transduction
- Squamous Cell Carcinoma of Head and Neck/genetics
- Squamous Cell Carcinoma of Head and Neck/immunology
- Squamous Cell Carcinoma of Head and Neck/metabolism
- Squamous Cell Carcinoma of Head and Neck/pathology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Time Factors
- Tumor Burden/drug effects
- Mice
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Affiliation(s)
- Jacob Gadwa
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Thomas E Bickett
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Laurel B Darragh
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michael William Knitz
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Shilpa Bhatia
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Miles Piper
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Benjamin Van Court
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Shiv Bhuvane
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Diemmy Nguyen
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Varuna Nangia
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Emily K Kleczko
- Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Raphael A Nemenoff
- Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Sana D Karam
- Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
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43
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Chen B, Zhou W, Tang C, Wang G, Yuan P, Zhang Y, Bhushan SC, Ma J, Leng J. Down-Regulation of C3aR/C5aR Inhibits Cell Proliferation and EMT in Hepatocellular Carcinoma. Technol Cancer Res Treat 2020; 19:1533033820970668. [PMID: 33176600 PMCID: PMC7672723 DOI: 10.1177/1533033820970668] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Complement 3a (C3a) and complement 5a (C5a), small cleavage fragments generated by complement activation, has been previously shown to be obviously up-regulated in highly metastatic hepatocellular carcinoma (HCC) cells. However, their functional roles in HCC cells remains unclear. Here, we investigated the biological function of G protein-coupled receptor C3aR/C5aR using small interference RNA in HCC cells. Our data showed that C3aR and C5aR knockdown significantly inhibited the proliferation, migration and invasion of HCC cells using CCK-8, colony formation and transwell assays. Flow cytometry assay showed C3aR and C5aR knockdown induced cell cycle G0/G1 phase arrest and apoptosis in HCC cells. Moreover, we found down-regulation of C3aR/C5aR obviously down-regulated the expression of PCNA, Ki-67 and suppressed the epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) in HCC cells. Collectively, our data demonstrated that targeting C3aR/C5aR may hold promise for the treatment of HCC.
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Affiliation(s)
- Bendong Chen
- Department of Hepatobiliary Surgery, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wenyan Zhou
- Department of ICU, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Chaofeng Tang
- Department of Hepatobiliary Surgery, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Genwang Wang
- Department of Hepatobiliary Surgery, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Peng Yuan
- Department of Hepatobiliary Surgery, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yawen Zhang
- 105002Ningxia Medical University, Yinchuan, Ningxia, China
| | | | - Jinlong Ma
- 105002Ningxia Medical University, Yinchuan, Ningxia, China
| | - Junzhi Leng
- Department of Hepatobiliary Surgery, 105002General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
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Zheng JM, Wang SS, Tian X, Che DJ. Sustained activation of C3aR in a human podocyte line impairs the morphological maturation of the cells. Mol Med Rep 2020; 22:5326-5338. [PMID: 33174024 PMCID: PMC7646996 DOI: 10.3892/mmr.2020.11626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 09/02/2020] [Indexed: 12/03/2022] Open
Abstract
The C3a receptor (C3aR) has been reported to be involved in various physiological and pathological processes, including the regulation of cellular structure development. Expression of C3aR has been reported in podocytes; however, data concerning the role of C3aR in podocyte morphology is scarce. The aim of the present study was to examine the effect of C3aR activation on the architectural development of podocytes. An immortal human podocyte line (HPC) was transfected with a C3a expression lentivirus vector or recombinant C3a. SB290157 was used to block the activation of C3aR. The expression of C3a in HPC cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR) and ELISAs. Phase contrast and fluorescence microscopy were used to observe the morphology of the podocytes. The adhesive ability of HPC cells was analyzed using an attachment assay. RT-qPCR, cyto-immunofluorescence and western blotting were used to determine the expression levels of the adhesion-associated genes. The expression levels of carboxypeptidases in HPC cells was also detected by RT-qPCR. Compared with the untransfected and control virus-transfected HPC cells, the C3a-overexpressing cells (HPC-C3a) failed to expand their cell bodies and develop an arborized appearance in the process of maturation, which the control cells exhibited. In addition, HPC-C3a cells presented with decreased adhesive capacity, altered focal adhesion (FA) plaques and decreased expression of FA-associated genes. These effects were blocked by a C3aR antagonist; however, the addition of purified C3a could not completely mimic the effects of C3a overexpression. Furthermore, HPC cells expressed carboxypeptidases, which have been reported to be able to inactivate C3a. In summary, the results demonstrated that sustained C3aR activation impaired the morphological maturation of HPC cells, which may be associated with the altered expression of FA-associated genes and impaired FA. Since chronic complement activation has been reported in renal diseases, which indicate sustained C3aR activation in renal cells, including podocytes and podocyte progenitors, the possible role of C3aR in the dysregulation of podocyte architecture and podocyte regeneration requires further research.
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Affiliation(s)
- Jing-Min Zheng
- Department of Nephrology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Sha-Sha Wang
- Department of Nephrology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Xiong Tian
- Department of Nephrology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - De-Jun Che
- Department of Nephrology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
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45
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Baier J, Gänsbauer M, Giessler C, Arnold H, Muske M, Schleicher U, Lukassen S, Ekici A, Rauh M, Daniel C, Hartmann A, Schmid B, Tripal P, Dettmer K, Oefner PJ, Atreya R, Wirtz S, Bogdan C, Mattner J. Arginase impedes the resolution of colitis by altering the microbiome and metabolome. J Clin Invest 2020; 130:5703-5720. [PMID: 32721946 PMCID: PMC7598089 DOI: 10.1172/jci126923] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Arginase 1 (Arg1), which converts l-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1fl/fl) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Arg1 deletion was reduced by an l-arginine-free diet, but rescued by simultaneous deletion of other l-arginine-metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires l-arginine. Fecal microbiota transfers from Tie2-Cre Arg1fl/fl mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of l-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.
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Affiliation(s)
- Julia Baier
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | | | - Claudia Giessler
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Harald Arnold
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Mercedes Muske
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Ulrike Schleicher
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | | | | | | | | | - Arndt Hartmann
- Pathologisches Institut, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Benjamin Schmid
- Optical Imaging Centre Erlangen (OICE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Philipp Tripal
- Optical Imaging Centre Erlangen (OICE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Katja Dettmer
- Institut für Funktionelle Genomik, Universität Regensburg, Regensburg, Germany
| | - Peter J. Oefner
- Institut für Funktionelle Genomik, Universität Regensburg, Regensburg, Germany
| | - Raja Atreya
- Medizinische Klinik 1–Gastroenterologie, Pneumologie and Endokrinologie, Universitätsklinikum Erlangen and FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1–Gastroenterologie, Pneumologie and Endokrinologie, Universitätsklinikum Erlangen and FAU Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Bogdan
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
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46
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Chauhan AJ, Wiffen LJ, Brown TP. COVID-19: A collision of complement, coagulation and inflammatory pathways. J Thromb Haemost 2020; 18:2110-2117. [PMID: 32608159 PMCID: PMC7361520 DOI: 10.1111/jth.14981] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.
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Affiliation(s)
- Anoop J Chauhan
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Faculty of Science and Health, University of Portsmouth, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
| | - Laura J Wiffen
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
| | - Thomas P Brown
- Research and Innovation, Queen Alexandra Hospital, Portsmouth, UK
- Respiratory Medicine, Queen Alexandra Hospital, Portsmouth, UK
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47
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Gao S, Cui Z, Zhao MH. The Complement C3a and C3a Receptor Pathway in Kidney Diseases. Front Immunol 2020; 11:1875. [PMID: 32973774 PMCID: PMC7461857 DOI: 10.3389/fimmu.2020.01875] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022] Open
Abstract
The pathogenesis of some kidney diseases is closely associated with complement activation, where the C3a/C3a receptor (C3aR) might play a crucial role. C3a/C3aR has dual roles and may exert anti-inflammatory or pro-inflammatory effects depending on different cell types and diseases. In the kidneys, C3aR is primarily expressed on the tubular epithelium and less in glomerular podocytes. C3aR expression is enhanced and the levels of C3a in the plasma and urine are increased in kidney diseases of several types, and are associated with disease progression and severity. The C3a/C3aR pathway facilitates the progression of glomerular and tubulointerstitial diseases, while it has opposite effects on urinary tract infections. Clinical trials targeting C3a/C3aR in kidney diseases are lacking. Here, we reviewed the studies on the C3a/C3aR pathway in kidney disease, with the aim of understanding in-depth its controversial roles and its potential therapeutic value.
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Affiliation(s)
- Shuang Gao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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48
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Rehman A, Baloch NUA, Morrow JP, Pacher P, Haskó G. Targeting of G-protein coupled receptors in sepsis. Pharmacol Ther 2020; 211:107529. [PMID: 32197794 PMCID: PMC7388546 DOI: 10.1016/j.pharmthera.2020.107529] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/11/2020] [Accepted: 03/11/2020] [Indexed: 12/11/2022]
Abstract
The Third International Consensus Definitions (Sepsis-3) define sepsis as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection. Sepsis can progress to septic shock-an even more lethal condition associated with profound circulatory, cellular and metabolic abnormalities. Septic shock remains a leading cause of death in intensive care units and carries a mortality of almost 25%. Despite significant advances in our understanding of the pathobiology of sepsis, therapeutic interventions have not translated into tangible differences in the overall outcome for patients. Clinical trials of antagonists of various pro-inflammatory mediators in sepsis have been largely unsuccessful in the past. Given the diverse physiologic roles played by G-protein coupled receptors (GPCR), modulation of GPCR signaling for the treatment of sepsis has also been explored. Traditional pharmacologic approaches have mainly focused on ligands targeting the extracellular domains of GPCR. However, novel techniques aimed at modulating GPCR intracellularly through aptamers, pepducins and intrabodies have opened a fresh avenue of therapeutic possibilities. In this review, we summarize the diverse roles played by various subfamilies of GPCR in the pathogenesis of sepsis and identify potential targets for pharmacotherapy through these novel approaches.
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Affiliation(s)
- Abdul Rehman
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ, United States
| | - Noor Ul-Ain Baloch
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ, United States
| | - John P Morrow
- Department of Medicine, Columbia University, New York City, NY, United States
| | - Pál Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York City, NY, United States.
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49
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Davidson S, Efremova M, Riedel A, Mahata B, Pramanik J, Huuhtanen J, Kar G, Vento-Tormo R, Hagai T, Chen X, Haniffa MA, Shields JD, Teichmann SA. Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth. Cell Rep 2020; 31:107628. [PMID: 32433953 PMCID: PMC7242909 DOI: 10.1016/j.celrep.2020.107628] [Citation(s) in RCA: 192] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/22/2020] [Accepted: 04/18/2020] [Indexed: 12/20/2022] Open
Abstract
Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR+ macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease.
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Affiliation(s)
- Sarah Davidson
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Mirjana Efremova
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Angela Riedel
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Bidesh Mahata
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Department of Pathology, University of Cambridge, Cambridge, UK
| | - Jhuma Pramanik
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Jani Huuhtanen
- Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Gozde Kar
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Roser Vento-Tormo
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Tzachi Hagai
- School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - Xi Chen
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Muzlifah A Haniffa
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Jacqueline D Shields
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cavendish Laboratory, University of Cambridge, JJ Thomson Ave, Cambridge CB3 0HE, UK.
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50
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Lo MW, Woodruff TM. Complement: Bridging the innate and adaptive immune systems in sterile inflammation. J Leukoc Biol 2020; 108:339-351. [PMID: 32182389 DOI: 10.1002/jlb.3mir0220-270r] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/07/2020] [Accepted: 02/19/2020] [Indexed: 12/24/2022] Open
Abstract
The complement system is a collection of soluble and membrane-bound proteins that together act as a powerful amplifier of the innate and adaptive immune systems. Although its role in infection is well established, complement is becoming increasingly recognized as a key contributor to sterile inflammation, a chronic inflammatory process often associated with noncommunicable diseases. In this context, damaged tissues release danger signals and trigger complement, which acts on a range of leukocytes to augment and bridge the innate and adaptive immune systems. Given the detrimental effect of chronic inflammation, the complement system is therefore well placed as an anti-inflammatory drug target. In this review, we provide a general outline of the sterile activators, effectors, and targets of the complement system and a series of examples (i.e., hypertension, cancer, allograft transplant rejection, and neuroinflammation) that highlight complement's ability to bridge the 2 arms of the immune system.
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Affiliation(s)
- Martin W Lo
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, Queensland, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, Queensland, Australia
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