Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin
2
조회
0
다운로드
1
인용
0
참고문헌
초록
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice with concurrent bleomycin injection. Blood, skin, and lung tissues were acquired and analyzed after PBMC engraftment. In addition, we investigated whether the humanized murine model could be used to assess the efficacy of potential therapeutics for SSc. Human PBMCs from SSc patients and healthy controls were engrafted into the blood, skin, and lung tissues of NSG mice. Histological analysis of affected tissues from mice treated with SSc PBMCs (SSc hu-mice) demonstrated substantial inflammation, fibrosis and vasculopathy with human immune cell infiltration and increased expression of IL-17, TGF-β, CCL2, CCL3, and CXCL9. The proportions of circulating and tissue-infiltrating T helper 17 (Th17) cells were elevated in SSc hu-mice. These cells showed increased expression of CXCR3 and phosphorylated STAT3. SSc hu-mice treated with rebamipide and other potential Th17-cell-modulating drugs presented significantly reduced tissue fibrosis. Mice injected with patient-derived PBMCs show promise as an animal model of SSc.
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice with concurrent bleomycin injection. Blood, skin, and lung tissues were acquired and analyzed after PBMC engraftment. In addition, we investigated whether the humanized murine model could be used to assess the efficacy of potential therapeutics for SSc. Human PBMCs from SSc patients and healthy controls were engrafted into the blood, skin, and lung tissues of NSG mice. Histological analysis of affected tissues from mice treated with SSc PBMCs (SSc hu-mice) demonstrated substantial inflammation, fibrosis and vasculopathy with human immune cell infiltration and increased expression of IL-17, TGF-β, CCL2, CCL3, and CXCL9. The proportions of circulating and tissue-infiltrating T helper 17 (Th17) cells were elevated in SSc hu-mice. These cells showed increased expression of CXCR3 and phosphorylated STAT3. SSc hu-mice treated with rebamipide and other potential Th17-cell-modulating drugs presented significantly reduced tissue fibrosis. Mice injected with patient-derived PBMCs show promise as an animal model of SSc.
참고문헌 (49)
- Denton, C. P., "Systemic sclerosis", Lancet, 390, pp.1685~1699 (2017)
- Allanore, Y., "Systemic sclerosis", Nat. Rev. Dis. Prim, 1, pp.15002~ (2015)
- Yamamoto, T., "Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma", J. Invest. Dermatol, 112, pp.456~462 (1999)
- Zhang, Y., "Murine sclerodermatous graft-versus-host disease, a model for human scleroderma : cutaneous cytokines, chemokines, and immune cell activation", J. Immunol, 168, pp.3088~3098 (2002)
- Asano, Y., "Transcription factor Fli1 regulates collagen fibrillogenesis in mouse skin", Mol. Cell Biol, 29, pp.425~434 (2009)
- Eferl, R., "Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2", AP-1, 2008, pp.105, 10525~10530
- Maurer, B., "Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis", Circulation, 120, pp.2367~2376 (2009)
- Jimenez, S. A., "Scleroderma-like alterations in collagen metabolism occurring in the TSK(tight skin)mouse", Arthritis Rheum, 27, pp.180~185 (1984)
- Teodoro, W. R., "Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL", 6 mice that reproduces fibrosis, vasculopathy and autoimmunity, 2019, pp.21, 278~
- Marangoni, R. G., "Animal models of scleroderma : recent progress", Curr. Opin. Rheumatol, 28, pp.561~570 (2016)
- Walsh, N. C., "Humanized mouse models of clinical disease", Annu. Rev. Pathol, 12, pp.187~215 (2017)
- Ishikawa, F., "Development of functional human blood and immune systems in NOD", SCID, Blood, pp.2005, 106[DOI]
- Katsumoto, T. R., "The pathogenesis of systemic sclerosis", Annu. Rev. Pathol, 6, pp.509~537 (2011)
- Bhattacharyya, S., "Understanding fibrosis in systemic sclerosis:shifting paradigms, emerging opportunities", Nat. Rev. Rheumatol, 8, pp.42~54 (2011)
- Ross, R. L., "Targeting human plasmacytoid dendritic cells through BDCA2prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma", Ann. Rheum. Dis, 80, pp.920~929 (2021)
- Shultz, L. D., "Human lymphoid and myeloid cell development in NOD", LtSzscid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells, 2005, pp.174, 6477~6489
- van den Hoogen, F., "2013 classification criteria for systemic sclerosis : an American College of Rheumatology", European League against Rheumatism collaborative initiative, 2013, pp.65, 2737~2747
- Böyum, A., "Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g", Scand. J. Clin. Lab. Invest. Suppl, 97, pp.77~89 (1968)
- Yue, X., "Transfer of PBMC From SSc Patients Induces Autoantibodies and Systemic Inflammation in Rag2-", -, -Mice, pp.Front. Immunol, 2021[DOI]
- Hübner, R. H., "Standardized quantification of pulmonary fibrosis in histological samples", Biotechniques, 44, pp.507~511 (2008)[DOI]
- Nishiwaki, S., "Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions", PLoS One, 9, pp.e96252~ (2014)
- Sharma, V., "Cur l 3, a major allergen of Curvularia lunataderived short synthetic peptides, shows promise for successful immunotherapy", Am. J. Respir. Cell Mol. Biol, 45, pp.1178~1184 (2011)
- Bergqvist, C., "Neutrophil extracellular traps are present in immune-complexmediated cutaneous small vessel vasculitis and correlate with the production of reactive oxygen species and the severity of vessel damage", Acta Derm. Venereol, 100, pp.adv00281~ (2020)
- Thannickal, V. J., "Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase", J. Biol. Chem, 278, pp.12384~12389 (2003)
- Abnaof, K., "TGF-β stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level", BMC Syst. Biol, 8, pp.55~55 (2014)
- Fossiez, F., "T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines", J. Exp. Med, 183, pp.2593~2603 (1996)
- Lipson, K. E., "CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis", Fibrogenes. Tissue Repair, 5, pp.S24~ (2012)
- Hinz, B., "Formation and function of the myofibroblast during tissue repair", J. Invest. Dermatol, 127, pp.526~537 (2007)
- Denton, C. P., "Targeted therapies for systemic sclerosis", Nat. Rev. Rheumatol, 9, pp.451~464 (2013)
- Distler, J. H., "Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis", Rheumatol. (Oxf.), 48, pp.98~103 (2009)
- Clark, K. E., "Multiplex cytokine analysis of dermal interstitial blister fluid defines local disease mechanisms in systemic sclerosis", Arthritis Res. Ther, 17, pp.73~ (2015)
- Carvalheiro, T., "Increased frequencies of circulating CXCL10-, CXCL8-and CCL4-producing monocytes and Siglec-3-expressing myeloid dendritic cells in systemic sclerosis patients", Inflamm. Res, 67, pp.169~177 (2018)
- Cossu, M., "Earliest phase of systemic sclerosis typified by increased levels of inflammatory proteins in the serum", Arthritis Rheumatol, 69, pp.2359~2369 (2017)
- Groom, J. R., "CXCR3 in T cell function", Exp. Cell Res, 317, pp.620~631 (2011)
- Kurasawa, K., "Increased interleukin-17 production in patients with systemic sclerosis", Arthritis Rheum, 43, pp.2455~2463 (2000)
- Rodríguez-Reyna, T. S., "Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness : a cross-sectional study", Rheumatol. Int, 32, pp.2653~2660 (2012)
- Yang, X., "Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction", Arthritis Res. Ther, 16, pp.R4~ (2014)
- Park, M. J., "IL-1-IL-17 signaling axis contributes to fibrosis and inflammation in two different murine models of systemic sclerosis", Front. Immunol, 9, pp.1611~ (2018)
- Cacciapaglia, F., "Phosphorylated signal transducer and activator of transcription 3(pSTAT3)is highly expressed in CD14+circulating cells of scleroderma patients", Rheumatol. (Oxf. ), 59, pp.1442~1444 (2020)
- Yang, X. O., "STAT3 regulates cytokine-mediated generation of inflammatory helper T cells", J. Biol. Chem, 282, pp.9358~9363 (2007)
- Chen, C. Z., "Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis state of the art", Fibrogenes. Tissue Repair, 2, pp.7~ (2009)
- Byun, J. K., "Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production", Clin. Exp. Immunol, 178, pp.9~19 (2014)
- Moon, S. J., "Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17", treg cell differentiation and heme oxygenase 1induction, 2014, pp.66, 874~885
- Min, H. K., "Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17", Treg cell imbalance in mice with curdlaninduced spondyloarthritis, 2016, pp.14, 190~
- Jin-Sil, P., "Immune modulation by rebamipide in a mouse model of Sjogren’s syndrome via T and B cell regulation", Immunol. Lett, 214, pp.1~7 (2019)
- Beyer, C., "Animal models of systemic sclerosis : prospects and limitations", Arthritis Rheum, 62, pp.2831~2844 (2010)
- Miyabe, Y., "Chemokines in rheumatic diseases : pathogenic role and therapeutic implications", Nat. Rev. Rheumatol, 15, pp.731~746 (2019)
- Truchetet, M. E., "Interleukin-17A+ cell counts are increased in systemic sclerosis skin and their number is inversely correlated with the extent of skin involvement", Arthritis Rheum, 65, pp.1347~1356 (2013)
- Nakashima, T., "Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts", J. Immunol, 188, pp.3573~3583 (2012)