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1
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Gao J, Li J, Luo Z, Wang H, Ma Z. Nanoparticle-Based Drug Delivery Systems for Inflammatory Bowel Disease Treatment. Drug Des Devel Ther 2024; 18:2921-2949. [PMID: 39055164 PMCID: PMC11269238 DOI: 10.2147/dddt.s461977] [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: 02/20/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory condition characterized by recurring inflammation of the intestinal mucosa. However, the existing IBD treatments are ineffective and have serious side effects. The etiology of IBD is multifactorial and encompasses immune, genetic, environmental, dietary, and microbial factors. The nanoparticles (NPs) developed based on specific targeting methodologies exhibit great potential as nanotechnology advances. Nanoparticles are defined as particles between 1 and 100 nm in size. Depending on their size and surface functionality, NPs exhibit different properties. A variety of nanoparticle types have been employed as drug carriers for the treatment of inflammatory bowel disease (IBD), with encouraging outcomes observed in experimental models. They increase the bioavailability of drugs and enable targeted drug delivery, promoting localized treatment and thus enhancing efficacy. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines.
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Affiliation(s)
- Jian Gao
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Jiannan Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Zengyou Luo
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Hongyong Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Zhiming Ma
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
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2
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Porras AM, Zhou H, Shi Q, Xiao X, Longman R, Brito IL. Inflammatory Bowel Disease-Associated Gut Commensals Degrade Components of the Extracellular Matrix. mBio 2022; 13:e0220122. [PMID: 36445085 PMCID: PMC9765649 DOI: 10.1128/mbio.02201-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/02/2022] [Indexed: 12/03/2022] Open
Abstract
Extracellular matrix (ECM) remodeling has emerged as a key feature of inflammatory bowel disease (IBD), and ECM fragments have been proposed as markers of clinical disease severity. Recent studies report increased protease activity in the gut microbiota of IBD patients. Nonetheless, the relationship between gut microbiota and ECM remodeling has remained unexplored. We hypothesized that members of the human gut microbiome could degrade the host ECM and that bacteria-driven remodeling, in turn, could enhance colonic inflammation. Through a variety of in vitro assays, we first confirmed that multiple bacterial species found in the human gut are capable of degrading specific ECM components. Clinical stool samples obtained from ulcerative colitis patients also exhibited higher levels of proteolytic activity in vitro, compared to those of their healthy counterparts. Furthermore, culture supernatants from bacteria species that are capable of degrading human ECM accelerated inflammation in dextran sodium sulfate (DSS)-induced colitis. Finally, we identified several of the bacterial proteases and carbohydrate degrading enzymes (CAZymes) that are potentially responsible for ECM degradation in vitro. Some of these protease families and CAZymes were also found in increased abundance in a metagenomic cohort of IBD. These results demonstrate that some commensal bacteria in the gut are indeed capable of degrading components of human ECM in vitro and suggest that this proteolytic activity may be involved in the progression of IBD. A better understanding of the relationship between nonpathogenic gut microbes, host ECM, and inflammation could be crucial to elucidating some of the mechanisms underlying host-bacteria interactions in IBD and beyond. IMPORTANCE Healthy gut epithelial cells form a barrier that keeps bacteria and other substances from entering the blood or tissues of the body. Those cells sit on scaffolding that maintains the structure of the gut and informs our immune system about the integrity of this barrier. In patients with inflammatory bowel disease (IBD), breaks are formed in this cellular barrier, and bacteria gain access to the underlying tissue and scaffolding. In our study, we discovered that bacteria that normally reside in the gut can modify and disassemble the underlying scaffolding. Additionally, we discovered that changes to this scaffolding affect the onset of IBD in mouse models of colitis as well as the abilities of these mice to recover. We propose that this new information will reveal how breaks in the gut wall lead to IBD and will open up new avenues by which to treat patients with IBD.
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Affiliation(s)
- Ana Maria Porras
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Hao Zhou
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Qiaojuan Shi
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Xieyue Xiao
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - JRI Live Cell Bank
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Randy Longman
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Ilana Lauren Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
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3
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Kotla NG, Singh R, Baby BV, Rasala S, Rasool J, Hynes SO, Martin D, Egan LJ, Vemula PK, Jala VR, Rochev Y, Pandit A. Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease. Biomaterials 2022; 281:121364. [DOI: 10.1016/j.biomaterials.2022.121364] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
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4
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Bosi A, Banfi D, Bistoletti M, Moretto P, Moro E, Crema F, Maggi F, Karousou E, Viola M, Passi A, Vigetti D, Giaroni C, Baj A. Hyaluronan: A Neuroimmune Modulator in the Microbiota-Gut Axis. Cells 2021; 11:cells11010126. [PMID: 35011688 PMCID: PMC8750446 DOI: 10.3390/cells11010126] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 12/22/2022] Open
Abstract
The commensal microbiota plays a fundamental role in maintaining host gut homeostasis by controlling several metabolic, neuronal and immune functions. Conversely, changes in the gut microenvironment may alter the saprophytic microbial community and function, hampering the positive relationship with the host. In this bidirectional interplay between the gut microbiota and the host, hyaluronan (HA), an unbranched glycosaminoglycan component of the extracellular matrix, has a multifaceted role. HA is fundamental for bacterial metabolism and influences bacterial adhesiveness to the mucosal layer and diffusion across the epithelial barrier. In the host, HA may be produced and distributed in different cellular components within the gut microenvironment, playing a role in the modulation of immune and neuronal responses. This review covers the more recent studies highlighting the relevance of HA as a putative modulator of the communication between luminal bacteria and the host gut neuro-immune axis both in health and disease conditions, such as inflammatory bowel disease and ischemia/reperfusion injury.
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Affiliation(s)
- Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Paola Moretto
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Fabrizio Maggi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Evgenia Karousou
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Manuela Viola
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Davide Vigetti
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
- Centre of Neuroscience, University of Insubria, 21100 Varese, Italy
- Correspondence: ; Tel.: +39-0332-217412; Fax: +39-0332-217111
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (M.B.); (P.M.); (F.M.); (E.K.); (M.V.); (A.P.); (D.V.); (A.B.)
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5
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Garantziotis S. Modulation of hyaluronan signaling as a therapeutic target in human disease. Pharmacol Ther 2021; 232:107993. [PMID: 34587477 DOI: 10.1016/j.pharmthera.2021.107993] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022]
Abstract
The extracellular matrix is an active participant, modulator and mediator of the cell, tissue, organ and organismal response to injury. Recent research has highlighted the role of hyaluronan, an abundant glycosaminoglycan constituent of the extracellular matrix, in many fundamental biological processes underpinning homeostasis and disease development. From this basis, emerging studies have demonstrated the therapeutic potential of strategies which target hyaluronan synthesis, biology and signaling, with significant promise as therapeutics for a variety of inflammatory and immune diseases. This review summarizes the state of the art in this field and discusses challenges and opportunities in what could emerge as a new class of therapeutic agents, that we term "matrix biologics".
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Affiliation(s)
- Stavros Garantziotis
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
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Hunt DR, Klett KC, Mascharak S, Wang H, Gong D, Lou J, Li X, Cai PC, Suhar RA, Co JY, LeSavage BL, Foster AA, Guan Y, Amieva MR, Peltz G, Xia Y, Kuo CJ, Heilshorn SC. Engineered Matrices Enable the Culture of Human Patient-Derived Intestinal Organoids. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004705. [PMID: 34026461 PMCID: PMC8132048 DOI: 10.1002/advs.202004705] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Indexed: 05/05/2023]
Abstract
Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin-like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue-derived, epithelial-only intestinal organoids. HELP enables the encapsulation of dissociated patient-derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal-derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin-ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid-matrix interactions and potential patient-specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G' ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10-3-1 × 10-3 m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal-derived products or synthetic polyethylene glycol for potential clinical translation.
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Affiliation(s)
- Daniel R. Hunt
- Department of Chemical EngineeringStanford UniversityStanfordCA94305USA
| | - Katarina C. Klett
- Department of Stem Cell Biology and Regenerative MedicineStanford UniversityStanfordCA94305USA
| | - Shamik Mascharak
- Department of BioengineeringStanford UniversityStanfordCA94305USA
| | - Huiyuan Wang
- Department of Materials Science & EngineeringStanford UniversityStanfordCA94305USA
| | - Diana Gong
- Department of BioengineeringStanford UniversityStanfordCA94305USA
| | - Junzhe Lou
- Department of ChemistryStanford UniversityStanfordCA94305USA
| | - Xingnan Li
- Department of Medicine and HematologyStanford University School of MedicineStanfordCA94305USA
| | - Pamela C. Cai
- Department of Chemical EngineeringStanford UniversityStanfordCA94305USA
| | - Riley A. Suhar
- Department of Materials Science & EngineeringStanford UniversityStanfordCA94305USA
| | - Julia Y. Co
- Department of Pediatrics (Infectious Diseases) and of Microbiology and ImmunologyStanford UniversityStanfordCA94305USA
| | | | - Abbygail A. Foster
- Department of Materials Science & EngineeringStanford UniversityStanfordCA94305USA
| | - Yuan Guan
- Department of AnesthesiologyStanford University School of MedicineStanfordCA94305USA
| | - Manuel R. Amieva
- Department of Pediatrics (Infectious Diseases) and of Microbiology and ImmunologyStanford UniversityStanfordCA94305USA
| | - Gary Peltz
- Department of AnesthesiologyStanford University School of MedicineStanfordCA94305USA
| | - Yan Xia
- Department of ChemistryStanford UniversityStanfordCA94305USA
| | - Calvin J. Kuo
- Department of Medicine and HematologyStanford University School of MedicineStanfordCA94305USA
| | - Sarah C. Heilshorn
- Department of Materials Science & EngineeringStanford UniversityStanfordCA94305USA
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7
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de Souza AB, Chaud MV, Santana MHA. Hyaluronic acid behavior in oral administration and perspectives for nanotechnology-based formulations: A review. Carbohydr Polym 2019; 222:115001. [PMID: 31320101 DOI: 10.1016/j.carbpol.2019.115001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/15/2019] [Accepted: 06/16/2019] [Indexed: 12/17/2022]
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Kotla NG, Burke O, Pandit A, Rochev Y. An Orally Administrated Hyaluronan Functionalized Polymeric Hybrid Nanoparticle System for Colon-Specific Drug Delivery. NANOMATERIALS 2019; 9:nano9091246. [PMID: 31480704 PMCID: PMC6780722 DOI: 10.3390/nano9091246] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 01/03/2023]
Abstract
There is a pressing clinical need for advanced colon-specific local drug delivery systems that can provide major advantages in treating diseases associated with the colon, such as inflammatory bowel disease (IBD) and colon cancer. A precise colon targeted drug delivery platform is expected to reduce drug side effects and increase the therapeutic response at the intended disease site locally. In this study, we report the fabrication of hyaluronan (HA) functionalized polymeric hybrid nanoparticulate system (Cur-HA NPs) by using curcumin as a model fluorescent drug. The Cur-HA NPs were about 200–300 nm in size, −51.3 mV overall surface charge after HA functionalization, with 56.0% drug released after 72 h in simulated gastrointestinal fluids. The Cur-HA NPs did not exhibit any cytotoxicity by AlamarBlue, PicoGreen and Live/Dead assays. Following the Cur-HA NPs use on HT-29 monolayer cell cultures demonstrating, the efficacy of HA functionalization increases cellular interaction, uptake when compared to uncoated nanoparticulate system. These findings indicate that HA functionalized nano-hybrid particles are effective in delivering drugs orally to the lower gastrointestinal tract (GIT) in order to treat local colonic diseases.
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Affiliation(s)
- Niranjan G Kotla
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway H91 W2TY, Ireland.
| | - Orla Burke
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway H91 W2TY, Ireland.
| | - Abhay Pandit
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway H91 W2TY, Ireland.
| | - Yury Rochev
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway H91 W2TY, Ireland.
- Sechenov First Moscow State Medical University, Institute for Regenerative Medicine, Moscow 119992, Russia.
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9
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Bellos DA, Sharma D, McMullen MR, Wat J, Saikia P, de la Motte CA, Nagy LE. Specifically Sized Hyaluronan (35 kDa) Prevents Ethanol-Induced Disruption of Epithelial Tight Junctions Through a layilin-Dependent Mechanism in Caco-2 Cells. Alcohol Clin Exp Res 2019; 43:1848-1858. [PMID: 31237689 DOI: 10.1111/acer.14140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Specific-sized species of the carbohydrate hyaluronan elicit a variety of cellular responses mediating tissue integrity and repair, as well as regulating inflammatory responses. Orally provided hyaluronan with an average molecular weight of 35 kDa (HA35) protects mice from short-term ethanol (EtOH)-induced liver injury. This protection was associated with maintenance of the colocalization of zonula occludens-1 (ZO-1) and occludin at tight junctions in the proximal colon. However, it is not known whether HA35 also protects other regions of the intestine or whether protection is due to a direct and/or indirect interaction of HA35 with the intestinal epithelium. METHODS Female C57BL/6J mice were fed an EtOH containing diet or pair-fed control diet (4 days) and treated with or without HA35 via daily gavage during the last 3 days of EtOH feeding. Intestinal morphology and tight junction integrity were assessed. Differentiated Caco-2 cells were transfected or not with scrambled siRNA or siRNA targeting layilin, a hyaluronan receptor. Caco-2 cells were treated with or without HA35 prior to challenge with EtOH. Localization of tight junction proteins, fluorescein isothiocyanate (FITC)-dextran permeability, and transepithelial electrical resistance (TEER) were evaluated. RESULTS While short-term EtOH did not result in any apparent changes in the gross morphology of the intestine, colocalization of ZO-1 and occludin at tight junctions was decreased in the proximal and distal colon. HA35 prevented these effects of EtOH. In differentiated Caco-2 cells, EtOH decreased the localization of ZO-1 and occludin at tight junctions and increased permeability of FITC-dextran. At higher concentrations, EtOH also decreased TEER. Pretreatment with HA35 prevented these changes. When the hyaluronan receptor layilin was knocked down in Caco-2 cells, HA35 no longer protected cells from EtOH-induced loss of tight junctions. CONCLUSIONS Taken together, these data indicate that HA35 interacts with layilin on intestinal epithelial cells and maintains intestinal tight junction integrity during short-term EtOH exposure.
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Affiliation(s)
- Damien A Bellos
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Dhara Sharma
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Megan R McMullen
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Jeanette Wat
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Paramananda Saikia
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Carol A de la Motte
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Laura E Nagy
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.,Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
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10
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/08/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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11
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Dokoshi T, Zhang LJ, Nakatsuji T, Adase CA, Sanford JA, Paladini RD, Tanaka H, Fujiya M, Gallo RL. Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin. JCI Insight 2018; 3:123072. [PMID: 30385720 DOI: 10.1172/jci.insight.123072] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 09/13/2018] [Indexed: 12/16/2022] Open
Abstract
In this study we evaluated the role of hyaluronan (HA) in reactive adipogenesis, a local expansion of preadipocytes that provides host defense by release of antimicrobial peptides. We observed that HA accumulated during maturation of adipocytes in vitro and was associated with increased expression of preadipocyte factor 1, zinc finger protein 423, and early B cell factor 1. Although HA is normally abundant in the extracellular matrix, a further increase in HA staining occurred in mice at sites of reactive adipogenesis following injury of colon by dextran sodium sulfate or injury of skin from infection with Staphylococcus aureus. HA also abundantly accumulated around adipocytes seen in the colons of patients with inflammatory bowel disease. This HA was necessary for adipocyte maturation because digestion of HA by administration of soluble hyaluronidase or transgenic expression of hyaluronidase 1 inhibited adipogenesis in vitro and in vivo. Furthermore, hyaluronidase also suppressed inflammation of both skin and colon and decreased antimicrobial peptide expression by developing preadipocytes. This resulted in increased bacterial transit across the epithelial barrier despite decreased tissue injury from inflammation. These observations suggest HA plays an important role in reactive adipogenesis and host defense after injury.
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Affiliation(s)
| | | | | | | | | | | | - Hiroki Tanaka
- Department of Legal Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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12
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Hauser-Kawaguchi A, Luyt LG, Turley E. Design of peptide mimetics to block pro-inflammatory functions of HA fragments. Matrix Biol 2018; 78-79:346-356. [PMID: 29408009 DOI: 10.1016/j.matbio.2018.01.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/22/2018] [Accepted: 01/28/2018] [Indexed: 12/26/2022]
Abstract
Hyaluronan is a simple extracellular matrix polysaccharide that actively regulates inflammation in tissue repair and disease processes. The native HA polymer, which is large (>500 kDa), contributes to the maintenance of homeostasis. In remodeling and diseased tissues, polymer size is strikingly polydisperse, ranging from <10 kDa to >500 kDa. In a diseased or stressed tissue context, both smaller HA fragments and high molecular weight HA polymers can acquire pro-inflammatory functions, which result in the activation of multiple receptors, triggering pro-inflammatory signaling to diverse stimuli. Peptide mimics that bind and scavenge HA fragments have been developed, which show efficacy in animal models of inflammation. These studies indicate both that HA fragments are key to driving inflammation and that scavenging these is a viable therapeutic approach to blunting inflammation in disease processes. This mini-review summarizes the peptide-based methods that have been reported to date for blocking HA signaling events as an anti-inflammatory therapeutic approach.
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Affiliation(s)
| | - Leonard G Luyt
- Department of Chemistry, Western University, London, ON, Canada; Department of Oncology, Schulich School of Medicine, Western University, London, ON, Canada; Department of Medical Imaging, Schulich School of Medicine, Western University, London, ON, Canada; Cancer Research Laboratories, London Regional Cancer Center, Victoria Hospital, London, ON N6A 4L6, Canada
| | - Eva Turley
- Department of Oncology, Schulich School of Medicine, Western University, London, ON, Canada; Cancer Research Laboratories, London Regional Cancer Center, Victoria Hospital, London, ON N6A 4L6, Canada; Department of Biochemistry, Schulich School of Medicine, Western University, London, ON, Canada; Department of Surgery, Schulich School of Medicine, Western University, London, ON, Canada.
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13
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Heldin P, Lin CY, Kolliopoulos C, Chen YH, Skandalis SS. Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production. Matrix Biol 2018; 78-79:100-117. [PMID: 29374576 DOI: 10.1016/j.matbio.2018.01.017] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/22/2018] [Accepted: 01/22/2018] [Indexed: 10/25/2022]
Abstract
The tightly regulated biosynthesis and catabolism of the glycosaminoglycan hyaluronan, as well as its role in organizing tissues and cell signaling, is crucial for the homeostasis of tissues. Overexpression of hyaluronan plays pivotal roles in inflammation and cancer, and markedly high serum and tissue levels of hyaluronan are noted under such pathological conditions. This review focuses on the complexity of the regulation at transcriptional and posttranslational level of hyaluronan synthetic enzymes, and the outcome of their aberrant expression and accumulation of hyaluronan in clinical conditions, such as systemic B-cell cancers, aggressive breast carcinomas, metabolic diseases and virus infection.
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Affiliation(s)
- Paraskevi Heldin
- Department Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
| | - Chun-Yu Lin
- Department Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Constantinos Kolliopoulos
- Department Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
| | - Yen-Hsu Chen
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin Chu, Taiwan
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
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14
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Filpa V, Bistoletti M, Caon I, Moro E, Grimaldi A, Moretto P, Baj A, Giron MC, Karousou E, Viola M, Crema F, Frigo G, Passi A, Giaroni C, Vigetti D. Changes in hyaluronan deposition in the rat myenteric plexus after experimentally-induced colitis. Sci Rep 2017; 7:17644. [PMID: 29247178 PMCID: PMC5732300 DOI: 10.1038/s41598-017-18020-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 12/05/2017] [Indexed: 12/27/2022] Open
Abstract
Myenteric plexus alterations hamper gastrointestinal motor function during intestinal inflammation. Hyaluronan (HA), an extracellular matrix glycosaminoglycan involved in inflammatory responses, may play a role in this process. In the colon of control rats, HA-binding protein (HABP), was detected in myenteric neuron soma, perineuronal space and ganglia surfaces. Prominent hyaluronan synthase 2 (HAS2) staining was found in myenteric neuron cytoplasm, suggesting that myenteric neurons produce HA. In the myenteric plexus of rats with 2, 4-dinitrobenzene sulfonic (DNBS)-induced colitis HABP staining was altered in the perineuronal space, while both HABP staining and HA levels increased in the muscularis propria. HAS2 immunopositive myenteric neurons and HAS2 mRNA and protein levels also increased. Overall, these observations suggest that inflammation alters HA distribution and levels in the gut neuromuscular compartment. Such changes may contribute to alterations in the myenteric plexus.
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Affiliation(s)
- Viviana Filpa
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Ilaria Caon
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Annalisa Grimaldi
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Paola Moretto
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Evgenia Karousou
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Manuela Viola
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Gianmario Frigo
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy.
| | - Davide Vigetti
- Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy
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15
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Saikia P, Bellos D, McMullen MR, Pollard KA, de la Motte C, Nagy LE. MicroRNA 181b-3p and its target importin α5 regulate toll-like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol. Hepatology 2017; 66:602-615. [PMID: 28257601 PMCID: PMC5519440 DOI: 10.1002/hep.29144] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/02/2017] [Accepted: 02/28/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED Increased inflammatory signaling by Kupffer cells contributes to alcoholic liver disease (ALD). Here we investigated the impact of small, specific-sized hyaluronic acid of 35 kD (HA35) on ethanol-induced sensitization of Kupffer cells, as well as ethanol-induced liver injury in mice. Unbiased analysis of microRNA (miRNA) expression in Kupffer cells identified miRNAs regulated by both ethanol and HA35. Toll-like receptor 4 (TLR4)-mediated signaling was assessed in primary cultures of Kupffer cells from ethanol- and pair-fed rats after treatment with HA35. Female C57BL6/J mice were fed ethanol or pair-fed control diets and treated or not with HA35. TLR4 signaling was increased in Kupffer cells by ethanol; this sensitization was normalized by ex vivo treatment with HA35. Next generation sequencing of Kupffer cell miRNA identified miRNA 181b-3p (miR181b-3p) as sensitive to both ethanol and HA35. Importin α5, a protein involved in p65 translocation to the nucleus, was identified as a target of miR181b-3p; importin α5 protein was increased in Kupffer cells from ethanol-fed rats, but decreased by HA35 treatment. Overexpression of miR181b-3p decreased importin α5 expression and normalized lipopolysaccharide-stimulated tumor necrosis factor α expression in Kupffer cells from ethanol-fed rats. In a mouse model of ALD, ethanol feeding decreased miR181b-3p in liver and increased expression of importin α5 in nonparenchymal cells. Treatment with HA35 normalized these changes and also protected mice from ethanol-induced liver and intestinal injury. CONCLUSION miR181b-3p is dynamically regulated in Kupffer cells and mouse liver in response to ethanol and treatment with HA35. miR181b-3p modulates expression of importin α5 and sensitivity of TLR4-mediated signaling. This study identifies a miR181b-3p-importin α5 axis in regulating inflammatory signaling pathways in hepatic macrophages. (Hepatology 2017;66:602-615).
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Affiliation(s)
- Paramananda Saikia
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Damien Bellos
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Megan R McMullen
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Katherine A Pollard
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Carol de la Motte
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Laura E Nagy
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.,Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
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16
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Hyaluronan mediates the adhesion of porcine peripheral blood mononuclear cells to poly (I:C)-treated intestinal cells and modulates their cytokine production. Vet Immunol Immunopathol 2016; 184:8-17. [PMID: 28166932 DOI: 10.1016/j.vetimm.2016.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/18/2016] [Accepted: 12/22/2016] [Indexed: 02/07/2023]
Abstract
Hyaluronan (HA), a major component of the extracellular matrix (ECM), has been increasingly recognized as a regulator of inflammation. Its role is complex since it has pro- and anti-inflammatory actions by modulating the expression of inflammatory genes, the recruitment of inflammatory cells and the production of inflammatory cytokines, but also by attenuating the course of inflammation and providing protection against tissue damage. Certain viruses and other inflammatory stimuli induce organization of HA into cable-like structures, which may be responsible for leukocyte recruitment and, on the other hand, low molecular weight fragments of HA have been shown to activate various inflammatory responses. The aim of the present study was to analyze the effects of a simulated infection with the viral mimetic Poly (I:C) on HA deposition on different porcine intestinal cells (primary colonic muscular smooth muscle cells (SMC), and epithelial IPEC-J2 and IPI-2I cell lines) and on the recruitment of peripheral blood mononuclear cells (PBMC) to intestinal cell layers. We show that Poly (I:C) treatment induces the formation of an HA-based pericellular matrix coat in muscular SMC and in intestinal epithelial cells (IECs) and that, on differentiated IPEC-J2 cells, HA accumulates in the basolateral membrane. Porcine PBMCs bind to Poly (I:C)-treated cells and this binding is dependent on HA, since the increase in adhesion is abolished by hyaluronidase treatment of the cell layers. A second goal was to study the effect of different molecular weight HA forms on the production of pro-inflammatory cytokines and chemokines (TNF-α, IL-1β and IL-8) by porcine PBMCs. Low molecular weight HA fragments (100-150kDa), in contrast to high molecular weight HA (2500kDa), stimulate the release of these pro-inflammatory mediators by porcine PBMCs. Our results suggest that HA is involved in the inflammatory response against pathogenic insults to the porcine gut.
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17
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Liang J, Jiang D, Noble PW. Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 2016; 97:186-203. [PMID: 26541745 PMCID: PMC4753080 DOI: 10.1016/j.addr.2015.10.017] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 10/19/2015] [Accepted: 10/20/2015] [Indexed: 02/07/2023]
Abstract
Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of hyaluronan depends on its size, location, and interactions with binding partners. While fragmented hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.
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Affiliation(s)
- Jiurong Liang
- Department of Medicine and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dianhua Jiang
- Department of Medicine and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Paul W Noble
- Department of Medicine and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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18
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Kolar SL, Kyme P, Tseng CW, Soliman A, Kaplan A, Liang J, Nizet V, Jiang D, Murali R, Arditi M, Underhill DM, Liu GY. Group B Streptococcus Evades Host Immunity by Degrading Hyaluronan. Cell Host Microbe 2015; 18:694-704. [PMID: 26651945 PMCID: PMC4683412 DOI: 10.1016/j.chom.2015.11.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 09/27/2015] [Accepted: 11/05/2015] [Indexed: 12/21/2022]
Abstract
In response to tissue injury, hyaluronan (HA) polymers are cleaved by host hyaluronidases, generating small fragments that ligate Toll-like receptors (TLRs) to elicit inflammatory responses. Pathogenic bacteria such as group B Streptococcus (GBS) express and secrete hyaluronidases as a mechanism for tissue invasion, but it is not known how this activity relates to immune detection of HA. We found that bacterial hyaluronidases secreted by GBS and other Gram-positive pathogens degrade pro-inflammatory HA fragments to their component disaccharides. In addition, HA disaccharides block TLR2/4 signaling elicited by both host-derived HA fragments and other TLR2/4 ligands, including lipopolysaccharide. Application of GBS hyaluronidase or HA disaccharides reduced pulmonary pathology and pro-inflammatory cytokine levels in an acute lung injury model. We conclude that breakdown of host-generated pro-inflammatory HA fragments to disaccharides allows bacterial pathogens to evade immune detection and could be exploited as a strategy to treat inflammatory diseases.
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Affiliation(s)
- Stacey L Kolar
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Pierre Kyme
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ching Wen Tseng
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Antoine Soliman
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Amber Kaplan
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jiurong Liang
- Division of Pulmonary, Department of Medicine, and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Victor Nizet
- Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Dianhua Jiang
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pulmonary, Department of Medicine, and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ramachandran Murali
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Moshe Arditi
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - David M Underhill
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - George Y Liu
- Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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