doi:10.3969/j.issn.1674-490X.2025.02.002

Abstract

Abstract: Interstitial lung disease associated with connective tissue disease(CTD-ILD), as one of the common interstitial lung diseases(ILD), is a common manifestation of connective tissue disease involving the lung. Its pathogenesis is complex and involves many influences. However, the process of pulmonary fibrosis caused by CTD-ILD is similar to that caused by other ILD. NLRP3 inflammasome is an intracellular sensing protein that can sense changes inside and outside the cell and mediate intense inflammation. Its activation is closely regulated by the body. Out-of-control inflammasome plays an important role in a variety of inflammation-related diseases. In recent years, many studies have confirmed the unique mechanism and clinical significance of inflammatory bodies in the pathogenesis and fibrosis of CTD-ILD, which is considered as a new target for the treatment of CTD-ILD. This study reviews the current research status of CTD-ILD, reviews the activation and regulatory mechanisms of inflammasome, and emphasizes the potential of inflammasome in the treatment of CTD-ILD, with a view to providing new ideas for the clinical treatment of CTD-ILD and blocking fibrosis with inflammasome.

Key words: connective tissue diseases, interstitial lung diseases, lung fibrosis, NLRP3 inflammasome

CLC Number:

References

[1] SOCIETY A T, SOCIETY E R. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society(ATS), and the European Respiratory Society(ERS)was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001[J]. Am J Respir Crit Care Med, 2002, 165(2): 277-304. DOI: 10.1164/ajrccm.165.2.ats01.
[2] COTTIN V, WOLLIN L, FISCHER A, et al. Fibrosing interstitial lung diseases: knowns and unknowns[J]. Eur Respir Rev, 2019, 28(151): 180100. DOI: 10.1183/16000617.0100-2018.
[3] THANNICKAL V J, TOEWS G B, WHITE E S, et al. Mechanisms of pulmonary fibrosis[J]. Annu Rev Med, 2004, 55: 395-417. DOI: 10.1146/annurev.med.55.091902.103810.
[4] RATHINAM V A, FITZGERALD K A. Inflammasome complexes: emerging mechanisms and effector functions[J]. Cell, 2016, 165(4): 792-800. DOI: 10.1016/j.cell.2016.03.046.
[5] DEMORUELLE M, MITTOO S, SOLOMON J J. Connective tissue disease-related interstitial lung disease[J].Best Pract Res Clin Rheumatol, 2016, 30(1): 39-52.DOI: 10.1016/j.berh.2016.04.006.
[6] PUTMAN R K, ROSAS I O, HUNNINGHAKE G M. Genetics and early detection in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med, 2014, 189(7): 770-8. DOI: 10.1164/rccm.201312-2219PP.
[7] JUGE P A, LEE J S, EBSTEIN E, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease[J]. N Engl J Med, 2018, 379(23): 2209-2219. DOI: 10.1056/NEJMoa1801562.
[8] BORIE R, CRESTANI B, DIEUDE P, et al. The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population[J]. PLoS One, 2013, 8(8): e70621. DOI: 10.1371/journal.pone.0070621.
[9] HOFFMAN T W, VAN MOORSEL C H M, BORIE R, et al. Pulmonary phenotypes associated with genetic variation in telomere-related genes[J]. Curr Opin Pulm Med, 2018, 24(3): 269-280. DOI: 10.1097/MCP.0000000000000475.
[10] NEWTON C A, BATRA K, TORREALBA J, et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive[J]. Eur Respir J, 2016, 48(6): 1710-1720. DOI: 10.1183/13993003.00308-2016.
[11] SNETSELAAR R, VAN MOORSEL C H M, KAZEMIER K M, et al. Telomere length in interstitial lung diseases[J]. Chest, 2015, 148(4): 1011-1018. DOI: 10.1378/chest.14-3078.
[12] SHAO T, SHI X, YANG S, et al. Interstitial lung disease in connective tissue disease: a common lesion with heterogeneous mechanisms and treatment considerations[J]. Front Immunol, 2021, 12: 684699. DOI: 10.3389/fimmu.2021.684699.
[13] RACANELLI A C, KIKKERS S A, CHOI A M K, et al. Autophagy and inflammation in chronic respiratory disease[J]. Autophagy, 2018, 14(2): 221-232. DOI: 10.1080/15548627.2017.1389823.
[14] SASAKI T, NAKAMURA W, INOKUMA S, et al. Characteristic features of tacrolimus-induced lung disease in rheumatoid arthritis patients[J]. Clin Rheumatol, 2016, 35(2): 541-545. DOI: 10.1007/s10067-015-2865-6.
[15] JUGE P A, LEE J S, LAU J, et al. Methotrexate and rheumatoid arthritis associated interstitial lung disease[J]. Eur Respir J, 2021, 57(2): 2000337. DOI: 10.1183/13993003.00337-2020.
[16] BAKER M C, LIU Y H, LU R, et al. Incidence of interstitial lung disease in patients with rheumatoid arthritis treated with biologic and targeted synthetic disease-modifying antirheumatic drugs[J]. JAMA Netw Open, 2023, 6(3): e233640. DOI: 10.1001/jamanetworkopen.2023.3640.
[17] AZADEH N, LIMPER A H, CARMONA E M, et al. The role of infection in interstitial lung diseases: a review[J]. Chest, 2017, 152(4): 842-852. DOI: 10.1016/j.chest.2017.03.033.
[18] DRAKOPANAGIOTAKIS F, STAVROPOULOU E, TSIGALOU C, et al. The role of the microbiome in connective-tissue-associated interstitial lung disease and pulmonary vasculitis[J]. Biomedicines, 2022, 10(12): 3195. DOI: 10.3390/biomedicines10123195.
[19] HAMBLY N, FAROOQI M, DVORKIN-GHEVA A, et al. Prevalence and characteristics of progressive fibrosing interstitial lung disease in a prospective registry[J]. Eur Respir J, 2022, 60(4): 2102571. DOI: 10.1183/13993003.02571-2021.
[20] JOY G M, ARBIV O A, WONG C K, et al. Prevalence, imaging patterns and risk factors of interstitial lung disease in connective tissue disease: a systematic review and meta-analysis[J]. Eur Respir Rev, 2023, 32(167): 220210. DOI: 10.1183/16000617.0210-2022.
[21] MATHAI S C, DANOFF S K. Management of interstitial lung disease associated with connective tissue disease[J]. BMJ, 2016, 352: h6819. DOI: 10.1136/bmj.h6819.
[22] WILSON T M, SOLOMON J J, DEMORUELLE M. Treatment approach to connective tissue disease-associated interstitial lung disease[J]. Curr Opin Pharmacol, 2022, 65: 102245. DOI: 10.1016/j.coph.2022.102245.
[23] HIGUERO SEVILLA J P, MEMON A, HINCHCLIFF M. Learnings from clinical trials in patients with connective tissue disease-associated interstitial lung disease[J]. Arthritis Res Ther, 2023, 25(1): 118. DOI: 10.1186/s13075-023-03090-y.
[24] GALEAS-PENA M, MCLAUGHLIN N, POCIASK D. The role of the innate immune system on pulmonary infections[J]. Biol Chem, 2019, 400(4): 443-456. DOI: 10.1515/hsz-2018-0304.
[25] TAKEUCHI O, AKIRA S. Pattern recognition receptors and inflammation[J]. Cell, 2010, 140(6): 805-20. DOI: 10.1016/j.cell.2010.01.022.
[26] MARTINON F, BURNS K, TSCHOPP J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta[J]. Mol Cell, 2002, 10(2): 417-26. DOI: 10.1016/s1097-2765(02)00599-3.
[27] BROZ P, DIXIT V M. Inflammasomes: mechanism of assembly, regulation and signalling[J]. Nat Rev Immunol, 2016, 16(7): 407-20. DOI: 10.1038/nri.2016.58.
[28] KELLEY N, JELTEMA D, DUAN Y, et al. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation[J]. Int J Mol Sci, 2019, 20(13): 3328. DOI: 10.3390/ijms20133328.
[29] NOONIN C, THONGBOONKERD V. Exosome-inflammasome crosstalk and their roles in inflammatory responses[J]. Theranostics, 2021, 11(9): 4436-4451. DOI: 10.7150/thno.54004.
[30] MATIKAINEN S, NYMAN T A, CYPRYK W. Function and regulation of noncanonical caspase-4/5/11 inflammasome[J]. J Immunol, 2020, 204(12): 3063-3069. DOI: 10.4049/jimmunol.2000373.
[31] PAIK S, KIM J K, SILWAL P, et al. An update on the regulatory mechanisms of NLRP3 inflammasome activation[J]. Cell Mol Immunol, 2021, 18(5): 1141-1160. DOI: 10.1038/s41423-021-00670-3.
[32] SONG H, LIU B, HUAI W, et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3[J]. Nat Commun, 2016, 7: 13727. DOI: 10.1038/ncomms13727.
[33] MOUTON-LIGER F, ROSAZZA T, SEPULVEDA-DIAZ J, et al. Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop[J]. Glia, 2018, 66(8): 1736-1751. DOI: 10.1002/glia.23337.
[34] WAN P, ZHANG Q, LIU W, et al. Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation[J]. FASEB J, 2019, 33(4): 5793-5807. DOI: 10.1096/fj.201801681R.
[35] SIU K L, YUEN K S, CASTAÑO-RODRIGUEZ C, et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC[J]. FASEB J, 2019, 33(8): 8865-8877. DOI: 10.1096/fj.201802418R.
[36] STUTZ A, KOLBE C C, STAHL R, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain[J]. J Exp Med, 2017, 214(6): 1725-1736. DOI: 10.1084/jem.20160933.
[37] MARTIN B N, WANG C, WILLETTE-BROWN J, et al. IKKα negatively regulates ASC-dependent inflammasome activation[J]. Nat Commun, 2014, 5: 4977. DOI: 10.1038/ncomms5977.
[38] SONG N, LIU Z S, XUE W, et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation[J]. Mol Cell, 2017, 68(1): 185-197. DOI: 10.1016/j.molcel.2017.08.017.
[39] KIM Y, LEE S, PARK Y H. NLRP3 negative regulation mechanisms in the resting state and its implications for therapeutic development[J]. Int J Mol Sci, 2024, 25(16): 9018. DOI: 10.3390/ijms25169018.
[40] ZHAO N, LI C C, DI B, et al. Recent advances in the NEK7-licensed NLRP3 inflammasome activation: mechanisms, role in diseases and related inhibitors[J]. J Autoimmun, 2020, 113: 102515. DOI: 10.1016/j.jaut.2020.102515.
[41] PERRI A. The NLRP3-inflammasome in health and disease[J]. Int J Mol Sci, 2022, 23(21): 13103. DOI: 10.3390/ijms232113103.
[42] SHARMA B R, KANNEGANTI T D. NLRP3 inflammasome in cancer and metabolic diseases[J]. Nat Immunol, 2021, 22(5): 550-559. DOI: 10.1038/s41590-021-00886-5.
[43] VOLKMANN E R, FISCHER A. Update on morbidity and mortality in systemic sclerosis-related interstitial lung disease[J]. J Scleroderma Relat Disord, 2021, 6(1): 11-20. DOI: 10.1177/2397198320915042.
[44] ARTLETT C M, SASSI-GAHA S, RIEGER J L, et al. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis[J]. Arthritis Rheum, 2011, 63(11): 3563-3574. DOI: 10.1002/art.30568.
[45] MARTÍNEZ-GODÍNEZ M A, CRUZ-DOMÍNGUEZ M P, JARA L J, et al. Expression of NLRP3 inflammasome, cytokines and vascular mediators in the skin of systemic sclerosis patients[J]. Isr Med Assoc J, 2015, 17(1): 5-10. PMID: 25739168
[46] ARTLETT C M, SASSI-GAHA S, HOPE J L, et al. miR-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis[J]. Arthritis Res Ther, 2017, 19(1): 144. DOI: 10.1186/s13075-017-1331-z.
[47] WOO S, GANDHI S, GHINCEA A, et al. Targeting the NLRP3 inflammasome and associated cytokines in Scleroderma associated interstitial lung disease[J]. Front Cell Dev Biol, 2023, 11: 1254904. DOI: 10.3389/fcell.2023.1254904.
[48] BOTTAI M, TJÄRNLUND A, SANTONI G, et al. EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a methodology report[J]. RMD Open, 2017, 3(2): e000507. DOI: 10.1136/rmdopen-2017-000507.
[49] DEETS K A, VANCE R E. Inflammasomes and adaptive immune responses[J]. Nat Immunol, 2021, 22(4): 412-422. DOI: 10.1038/s41590-021-00869-6.
[50] MA M, CHAI K, DENG R. Study of the correlation between the noncanonical pathway of pyroptosis and idiopathic inflammatory myopathy[J]. Int Immunopharmacol, 2021, 98: 107810. DOI: 10.1016/j.intimp.2021.107810.
[51] LIU D, XIAO Y, ZHOU B, et al. PKM2-dependent glycolysis promotes skeletal muscle cell pyroptosis by activating the NLRP3 inflammasome in dermatomyositis/polymyositis[J]. Rheumatology(Oxford), 2021, 60(5): 2177-2189. DOI: 10.1093/rheumatology/keaa473.
[52] NADDAF E, NGUYEN T K O, WATZLAWIK J O, et al. NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis[J]. J Cachexia Sarcopenia Muscle, 2025,16(1):e13672. DOI: 10.1002/jcsm.13672.2024.06.15.24308845.
[53] JABLONSKI R, BHORADE S, STREK M E, et al. Recognition and management of myositis-associated rapidly progressive interstitial lung disease[J]. Chest, 2020, 158(1): 252-263. DOI: 10.1016/j.chest.2020.01.033.
[54] 马文兰.中性粒细胞胞外诱捕网诱导肺微血管内皮细胞间质转化在皮肌炎相关间质性肺病中的致病机制[D].兰州:兰州大学, 2023: 1-54.
[55] LASITHIOTAKI I, GIANNARAKIS I, TSITOURA E, et al. NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung[J]. Eur Respir J, 2016, 47(3): 910-918. DOI: 10.1183/13993003.00564-2015.
[56] JIANG Q, WANG X, HUANG E, et al. Inflammasome and its therapeutic targeting in rheumatoid arthritis[J]. Front Immunol, 2022, 12: 816839. DOI: 10.3389/fimmu.2021.816839.
[57] VAKRAKOU A G, BOIU S, ZIAKAS P D, et al. Systemic activation of NLRP3 inflammasome in patients with severe primary Sjögren's syndrome fueled by inflammagenic DNA accumulations[J]. J Autoimmun, 2018, 91: 23-33. DOI: 10.1016/j.jaut.2018.02.010.
[58] KIRIPOLSKY J, MCCABE L G, GAILE D P, et al. Myd88 is required for disease development in a primary Sjögren's syndrome mouse model[J]. J Leukoc Biol, 2017, 102(6): 1411-1420. DOI: 10.1189/jlb.3A0717-311R.

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