Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Immune Mechanisms and Related Targets for the Treatment of Fibrosis in Various Organs

Author(s): Anita A. Pinar* and Chrishan S. Samuel*

Volume 22, Issue 3, 2022

Published on: 16 February, 2022

Page: [240 - 249] Pages: 10

DOI: 10.2174/1566524022666220114122839

Price: $65

Abstract

Inflammation and fibrosis are two interrelated disease pathologies with several overlapping components. Three specific cell types, namely macrophages, T helper cells, and myofibroblasts, play important roles in regulating both processes. Following tissue injury, an inflammatory stimulus is often necessary to initiate tissue repair, where cytokines released from infiltrating and resident immune and inflammatory cells stimulate the proliferation and activation of extracellular matrix-producing myofibroblasts. However, persistent tissue injury drives an inappropriate pro‐fibrotic response. Additionally, activated myofibroblasts can take on the role of traditional antigen-presenting cells, secrete pro-inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Moreover, inflammatory cells have been shown to play contradictory roles in the initiation, amplification, and resolution of fibrotic disease processes. The central role of the inflammasome molecular platform in contributing to fibrosis is only beginning to be fully appreciated. In this review, we discuss the immune mechanisms that can lead to fibrosis, the inflammasomes that have been implicated in the fibrotic process in the context of the immune response to injury, and also discuss current and emerging therapies that target inflammasome-induced collagen deposition to treat organ fibrosis.

Keywords: Immune mechanisms, inflammasomes, NLRP3 inflammasome, myofibroblast differentiation, collagen deposition, fibrosis.

« Previous Next »
[1]
Wynn TA, Ramalingam TR. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med 2012; 18(7): 1028-40.
[http://dx.doi.org/10.1038/nm.2807] [PMID: 22772564]
[2]
Henderson NC, Rieder F, Wynn TA. Fibrosis: From mechanisms to medicines. Nature 2020; 587(7835): 555-66.
[http://dx.doi.org/10.1038/s41586-020-2938-9] [PMID: 33239795]
[3]
Lorenz G, Darisipudi MN, Anders HJ. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant 2014; 29(1): 41-8.
[http://dx.doi.org/10.1093/ndt/gft332] [PMID: 24026244]
[4]
Lichtman MK, Otero-Vinas M, Falanga V. Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis. Wound Repair Regen 2016; 24(2): 215-22.
[http://dx.doi.org/10.1111/wrr.12398] [PMID: 26704519]
[5]
Mori T, Kawara S, Shinozaki M, et al. Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol 1999; 181(1): 153-9.
[http://dx.doi.org/10.1002/(SICI)1097-4652(199910)181:1<153:AID-JCP16>3.0.CO;2-K] [PMID: 10457363]
[6]
Wang Q, Usinger W, Nichols B, et al. Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease. Fibrogenesis Tissue Repair 2011; 4(1): 4.
[http://dx.doi.org/10.1186/1755-1536-4-4] [PMID: 21284856]
[7]
Leask A, Abraham DJ. All in the CCN family: Essential matricellular signaling modulators emerge from the bunker. J Cell Sci 2006; 119(Pt 23): 4803-10.
[http://dx.doi.org/10.1242/jcs.03270] [PMID: 17130294]
[8]
Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2001; 21(3): 351-72.
[http://dx.doi.org/10.1055/s-2001-17556] [PMID: 11586465]
[9]
Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 2016; 365(3): 563-81.
[http://dx.doi.org/10.1007/s00441-016-2431-9] [PMID: 27324127]
[10]
Wick G, Backovic A, Rabensteiner E, Plank N, Schwentner C, Sgonc R. The immunology of fibrosis: Innate and adaptive responses. Trends Immunol 2010; 31(3): 110-9.
[http://dx.doi.org/10.1016/j.it.2009.12.001] [PMID: 20106721]
[11]
Gasse P, Riteau N, Charron S, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med 2009; 179(10): 903-13.
[http://dx.doi.org/10.1164/rccm.200808-1274OC] [PMID: 19218193]
[12]
Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007; 178(8): 5288-95.
[http://dx.doi.org/10.4049/jimmunol.178.8.5288] [PMID: 17404313]
[13]
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5(12): 953-64.
[http://dx.doi.org/10.1038/nri1733] [PMID: 16322748]
[14]
Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest 2012; 122(3): 787-95.
[http://dx.doi.org/10.1172/JCI59643] [PMID: 22378047]
[15]
Wynn TA, Barron L. Macrophages: Master regulators of inflammation and fibrosis. Semin Liver Dis 2010; 30(3): 245-57.
[http://dx.doi.org/10.1055/s-0030-1255354] [PMID: 20665377]
[16]
Eardley KS, Zehnder D, Quinkler M, et al. The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int 2006; 69(7): 1189-97.
[http://dx.doi.org/10.1038/sj.ki.5000212] [PMID: 16609683]
[17]
Koh TJ, DiPietro LA. Inflammation and wound healing: The role of the macrophage. Expert Rev Mol Med 2011; 13: e23.
[http://dx.doi.org/10.1017/S1462399411001943] [PMID: 21740602]
[18]
Lech M, Anders HJ. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta 2013; 1832(7): 989-97.
[http://dx.doi.org/10.1016/j.bbadis.2012.12.001] [PMID: 23246690]
[19]
Tan TK, Zheng G, Hsu TT, et al. Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage. Lab Invest 2013; 93(4): 434-49.
[http://dx.doi.org/10.1038/labinvest.2013.3] [PMID: 23358111]
[20]
Levi-Schaffer F, Piliponsky AM. Tryptase, a novel link between allergic inflammation and fibrosis. Trends Immunol 2003; 24(4): 158-61.
[http://dx.doi.org/10.1016/S1471-4906(03)00058-9] [PMID: 12697439]
[21]
Rao KN, Brown MA. Mast cells: Multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci 2008; 1143(1): 83-104.
[http://dx.doi.org/10.1196/annals.1443.023] [PMID: 19076346]
[22]
Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: A novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol 2007; 1(1): 173-80.
[http://dx.doi.org/10.1586/17474124.1.1.173] [PMID: 19072444]
[23]
Kim JH, Kim HY, Kim S, Chung JH, Park WS, Chung DH. Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-gamma. Am J Pathol 2005; 167(5): 1231-41.
[http://dx.doi.org/10.1016/S0002-9440(10)61211-4] [PMID: 16251408]
[24]
Castagnoli C, Trombotto C, Ondei S, et al. Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues. Burns 1997; 23(7-8): 565-72.
[http://dx.doi.org/10.1016/S0305-4179(97)00070-3] [PMID: 9568325]
[25]
Gruber R, Pforte A, Beer B, Riethmüller G. Determination of gamma/delta and other T-lymphocyte subsets in bronchoalveolar lavage fluid and peripheral blood from patients with sarcoidosis and idiopathic fibrosis of the lung. Acta Pathol Microbiol Scand Suppl 1996; 104(3): 199-205.
[http://dx.doi.org/10.1111/j.1699-0463.1996.tb00708.x] [PMID: 8611194]
[26]
Prakobwong S, Pinlaor S, Yongvanit P, Sithithaworn P, Pairojkul C, Hiraku Y. Time profiles of the expression of metalloproteinases, tissue inhibitors of metalloproteases, cytokines and collagens in hamsters infected with Opisthorchis viverrini with special reference to peribiliary fibrosis and liver injury. Int J Parasitol 2009; 39(7): 825-35.
[http://dx.doi.org/10.1016/j.ijpara.2008.12.002] [PMID: 19168069]
[27]
Rottoli P, Magi B, Perari MG, et al. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 2005; 5(5): 1423-30.
[http://dx.doi.org/10.1002/pmic.200301007] [PMID: 15761959]
[28]
Fuschiotti P, Medsger TA Jr, Morel PA. Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin-13 associated with increased skin fibrosis. Arthritis Rheum 2009; 60(4): 1119-28.
[http://dx.doi.org/10.1002/art.24432] [PMID: 19333920]
[29]
Wangoo A, Sparer T, Brown IN, et al. Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease. J Immunol 2001; 166(5): 3432-9.
[http://dx.doi.org/10.4049/jimmunol.166.5.3432] [PMID: 11207301]
[30]
Kurasawa K, Hirose K, Sano H, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000; 43(11): 2455-63.
[http://dx.doi.org/10.1002/1529-0131(200011)43:11<2455:AID-ANR12>3.0.CO;2-K] [PMID: 11083268]
[31]
Braun RK, Ferrick C, Neubauer P, et al. IL-17 producing gammadelta T cells are required for a controlled inflammatory response after bleomycin-induced lung injury. Inflammation 2008; 31(3): 167-79.
[http://dx.doi.org/10.1007/s10753-008-9062-6] [PMID: 18338242]
[32]
Ouyang X, Ghani A, Mehal WZ. Inflammasome biology in fibrogenesis. Biochim Biophys Acta 2013; 1832(7): 979-88.
[http://dx.doi.org/10.1016/j.bbadis.2013.03.020] [PMID: 23562491]
[33]
Pinar AA, Scott TE, Huuskes BM, Tapia Cáceres FE, Kemp-Harper BK, Samuel CS. Targeting the NLRP3 inflammasome to treat cardiovascular fibrosis. Pharmacol Ther 2020; 209: 107511.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107511] [PMID: 32097669]
[34]
Krishnan SM, Dowling JK, Ling YH, et al. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol 2016; 173(4): 752-65.
[http://dx.doi.org/10.1111/bph.13230] [PMID: 26103560]
[35]
Pinar AA, Yuferov A, Gaspari TA, Samuel CS. Relaxin can mediate its anti-fibrotic effects by targeting the myofibroblast NLRP3 inflammasome at the level of caspase-1. Front Pharmacol 2020; 11: 1201.
[http://dx.doi.org/10.3389/fphar.2020.01201] [PMID: 32848798]
[36]
Cáceres FT, Gaspari TA, Samuel CS, Pinar AA. Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts. FASEB J 2019; 33(12): 14717-33.
[http://dx.doi.org/10.1096/fj.201901079RR] [PMID: 31689135]
[37]
Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 2002; 10(2): 417-26.
[http://dx.doi.org/10.1016/S1097-2765(02)00599-3] [PMID: 12191486]
[38]
Iversen L, Johansen C. Inflammasomes and inflammatory caspases in skin inflammation. Expert Rev Mol Diagn 2008; 8(6): 697-705.
[http://dx.doi.org/10.1586/14737159.8.6.697] [PMID: 18999922]
[39]
Christo SN, Diener KR, Manavis J, et al. Inflammasome components ASC and AIM2 modulate the acute phase of biomaterial implant-induced foreign body responses. Sci Rep 2016; 6(1): 20635.
[http://dx.doi.org/10.1038/srep20635] [PMID: 26860464]
[40]
Kuwano K, Hagimoto N, Hara N. Molecular mechanisms of pulmonary fibrosis and current treatment. Curr Mol Med 2001; 1(5): 551-73.
[http://dx.doi.org/10.2174/1566524013363401] [PMID: 11899231]
[41]
Gasse P, Mary C, Guenon I, et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 2007; 117(12): 3786-99.
[http://dx.doi.org/10.1172/JCI32285] [PMID: 17992263]
[42]
Couillin I, Vasseur V, Charron S, et al. IL-1R1/MyD88 signaling is critical for elastase-induced lung inflammation and emphysema. J Immunol 2009; 183(12): 8195-202.
[http://dx.doi.org/10.4049/jimmunol.0803154] [PMID: 20007584]
[43]
Benson HL, Wilkes DS. Matrix metalloproteinases in T cell mediated pulmonary diseases. Front Biosci (Elite Ed) 2012; 4(6): 2162-9.
[http://dx.doi.org/10.2741/e533] [PMID: 22202028]
[44]
Menou A, Duitman J, Crestani B. The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis. Matrix Biol 2018; 68-69: 382-403.
[http://dx.doi.org/10.1016/j.matbio.2018.03.001] [PMID: 29518524]
[45]
Friedman SL. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88(1): 125-72.
[http://dx.doi.org/10.1152/physrev.00013.2007] [PMID: 18195085]
[46]
Watanabe A, Sohail MA, Gomes DA, et al. Inflammasome-mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2009; 296(6): G1248-57.
[http://dx.doi.org/10.1152/ajpgi.90223.2008] [PMID: 19359429]
[47]
Gieling RG, Wallace K, Han YP. Interleukin-1 participates in the progression from liver injury to fibrosis. Am J Physiol Gastrointest Liver Physiol 2009; 296(6): G1324-31.
[http://dx.doi.org/10.1152/ajpgi.90564.2008] [PMID: 19342509]
[48]
Bhattacharyya S, Wei J, Tourtellotte WG, Hinchcliff M, Gottardi CG, Varga J. Fibrosis in systemic sclerosis: Common and unique pathobiology. Fibrogenesis Tissue Repair 2012; 5(S1)(Suppl. 1): S18.
[http://dx.doi.org/10.1186/1755-1536-5-S1-S18] [PMID: 23259815]
[49]
LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: A possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest 1974; 54(4): 880-9.
[http://dx.doi.org/10.1172/JCI107827] [PMID: 4430718]
[50]
Vuorio TK, Kähäri VM, Lehtonen A, Vuorio EI. Fibroblast activation in scleroderma. Scand J Rheumatol 1984; 13(3): 229-37.
[http://dx.doi.org/10.3109/03009748409100391] [PMID: 6484539]
[51]
Kähäri VM, Sandberg M, Kalimo H, Vuorio T, Vuorio E. Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol 1988; 90(5): 664-70.
[http://dx.doi.org/10.1111/1523-1747.ep12560826] [PMID: 3361141]
[52]
Scharffetter K, Lankat-Buttgereit B, Krieg T. Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest 1988; 18(1): 9-17.
[http://dx.doi.org/10.1111/j.1365-2362.1988.tb01158.x] [PMID: 3130266]
[53]
Kawaguchi Y. IL-1 alpha gene expression and protein production by fibroblasts from patients with systemic sclerosis. Clin Exp Immunol 1994; 97(3): 445-50.
[http://dx.doi.org/10.1111/j.1365-2249.1994.tb06108.x] [PMID: 8082299]
[54]
Feghali CA, Bost KL, Boulware DW, Levy LS. Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. J Rheumatol 1992; 19(8): 1207-11.
[PMID: 1404155]
[55]
Artlett CM, Sassi-Gaha S, Rieger JL, Boesteanu AC, Feghali-Bostwick CA, Katsikis PD. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum 2011; 63(11): 3563-74.
[http://dx.doi.org/10.1002/art.30568] [PMID: 21792841]
[56]
Kawaguchi M, Takahashi M, Hata T, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 2011; 123(6): 594-604.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.982777] [PMID: 21282498]
[57]
Song E, Jahng JW, Chong LP, et al. Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge. Am J Transl Res 2017; 9(6): 2723-35.
[PMID: 28670364]
[58]
Krishnan SM, Ling YH, Huuskes BM, et al. Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc Res 2019; 115(4): 776-87.
[http://dx.doi.org/10.1093/cvr/cvy252] [PMID: 30357309]
[59]
Li S, Lin Q, Shao X, et al. NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation. Exp Cell Res 2019; 383(1): 111488.
[http://dx.doi.org/10.1016/j.yexcr.2019.07.001] [PMID: 31276670]
[60]
Alyaseer AAA, de Lima MHS, Braga TT. The role of NLRP3 inflammasome activation in the epithelial to mesenchymal transition process during the fibrosis. Front Immunol 2020; 11: 883.
[http://dx.doi.org/10.3389/fimmu.2020.00883] [PMID: 32508821]
[61]
Lv Z, Wang Y, Liu YJ, et al. NLRP3 inflammasome activation contributes to mechanical stretch-induced endothelial-mesenchymal transition and pulmonary fibrosis. Crit Care Med 2018; 46(1): e49-58.
[http://dx.doi.org/10.1097/CCM.0000000000002799] [PMID: 29088003]
[62]
Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015; 21(3): 248-55.
[http://dx.doi.org/10.1038/nm.3806] [PMID: 25686105]
[63]
Mridha AR, Wree A, Robertson AAB, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol 2017; 66(5): 1037-46.
[http://dx.doi.org/10.1016/j.jhep.2017.01.022] [PMID: 28167322]
[64]
Gao R, Shi H, Chang S, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharmacol 2019; 74: 105575.
[http://dx.doi.org/10.1016/j.intimp.2019.04.022] [PMID: 31299609]
[65]
Kuwano K, Kunitake R, Maeyama T, et al. Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2001; 280(2): L316-25.
[http://dx.doi.org/10.1152/ajplung.2001.280.2.L316] [PMID: 11159011]
[66]
Abbate A, Salloum FN, Vecile E, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 2008; 117(20): 2670-83.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.740233] [PMID: 18474815]
[67]
Ling YH, Krishnan SM, Chan CT, et al. Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. Pharmacol Res 2017; 116: 77-86.
[http://dx.doi.org/10.1016/j.phrs.2016.12.015] [PMID: 27986554]
[68]
Meier RPH, Meyer J, Montanari E, et al. Interleukin-1 receptor antagonist modulates liver inflammation and fibrosis in mice in a model-dependent manner. Int J Mol Sci 2019; 20(6): 1295.
[http://dx.doi.org/10.3390/ijms20061295] [PMID: 30875826]
[69]
Samuel CS, Royce SG, Hewitson TD, Denton KM, Cooney TE, Bennett RG. Anti-fibrotic actions of relaxin. Br J Pharmacol 2017; 174(10): 962-76.
[http://dx.doi.org/10.1111/bph.13529] [PMID: 27250825]
[70]
Samuel CS, Summers RJ, Hewitson TD. Antifibrotic actions of serelaxin - New roles for an old player. Trends Pharmacol Sci 2016; 37(6): 485-97.
[http://dx.doi.org/10.1016/j.tips.2016.02.007] [PMID: 26996448]
[71]
Unemori EN, Amento EP. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 1990; 265(18): 10681-5.
[http://dx.doi.org/10.1016/S0021-9258(18)87000-4] [PMID: 2162358]

Rights & Permissions Print Cite
Article Metrics
30
2
© 2024 Bentham Science Publishers | Privacy Policy