Monocyte–macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti-melanoma differentiation-associated gene 5-positive dermatomyositis-related interstitial lung disease

Abstract

	•Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD.
	•Circulating monocytes transition from an immunosuppressive phenotype in the periphery to proinflammatory and profibrotic Mo-AMs in the lungs.
	•Chemokines produced by Mo-AMs drive monocyte and other immune cell recruitment to the lungs, amplifying pulmonary inflammation.

Keywords

anti-MDA5 Antibody / dermatomyositis / macrophage / monocyte / single-cell analysis

References

[1] NombelA, FabienN, CoutantF. Dermatomyositis with anti-MDA5 antibodies: bioclinical features, pathogenesis and emerging therapies. Front Immunol. 2021; 12: 773352.

[2] HaliluF, Christopher-Stine L. Myositis-specific antibodies: overview and clinical utilization. Rheumatol Immunol Res. 2022; 3(1): 1-10.

[3] KatoH, Takeuchi O, SatoS, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006; 441(7089): 101-105.

[4] YinX, RivaL, PuY, et al. MDA5 governs the innate immune response to SARS-CoV-2 in lung epithelial cells. Cell Rep. 2021; 34(2): 108628.

[5] ZhouZ, RenL, ZhangL, et al. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe. 2020; 27(6): 883-890.e2.

[6] GianniniM, OhanaM, NespolaB, et al. Similarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care? Eur Respir J. 2020; 56(3)

[7] WangG, WangQ, WangY, et al. Presence of anti-MDA5 antibody and its value for the clinical assessment in patients with COVID-19: a retrospective cohort study. Front Immunol. 2021; 12: 791348.

[8] GonoT, Kawaguchi Y, SatohT, et al. Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis. Rheumatology (Oxford). 2010; 49(9): 1713-1719.

[9] ZuoY, YeL, ChenF, et al. Different multivariable risk factors for rapid progressive interstitial lung disease in anti-MDA5 positive dermatomyositis and anti-synthetase syndrome. Front Immunol. 2022; 13: 845988.

[10] PengQL, ZhangYM, LiangL, et al. A high level of serum neopterin is associated with rapidly progressive interstitial lung disease and reduced survival in dermatomyositis. Clin Exp Immunol. 2020; 199(3): 314-325.

[11] FujisawaT, HozumiH, YasuiH, et al. Clinical significance of serum chitotriosidase level in anti-MDA5 antibody-positive dermatomyositis-associated interstitial lung disease. J Rheumatol. 2019; 46(8): 935-942.

[12] HoriikeY, SuzukiY, FujisawaT, et al. Successful classification of macrophage-mannose receptor CD206 in severity of anti-MDA5 antibody positive dermatomyositis associated ILD. Rheumatology (Oxford). 2019; 58(12): 2143-2152.

[13] PengQL, ZhangYL, ShuXM, et al. Elevated serum levels of soluble CD163 in polymyositis and dermatomyositis: associated with macrophage infiltration in muscle tissue. J Rheumatol. 2015; 42(6): 979-87.

[14] ShirakashiM, Nakashima R, TsujiH, et al. Efficacy of plasma exchange in anti-MDA5-positive dermatomyositis with interstitial lung disease under combined immunosuppressive treatment. Rheumatology (Oxford). 2020; 59(11): 3284-3292.

[15] CrayneCB, Albeituni S, NicholsKE, et al. The immunology of macrophage activation syndrome. Front Immunol. 2019; 10: 119.

[16] ZuoY, YeL, LiuM, et al. Clinical significance of radiological patterns of HRCT and their association with macrophage activation in dermatomyositis. Rheumatology (Oxford). 2020; 59(10): 2829-2837.

[17] GonoT, Okazaki Y, KuwanaM. Antiviral proinflammatory phenotype of monocytes in anti-MDA5 antibody-associated interstitial lung disease. Rheumatology (Oxford). 2022; 61(2): 806-814.

[18] YeY, ChenZ, JiangS, et al. Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications. Nat Commun. 2022; 13(1).

[19] JinQ, FuL, YangH, et al. Peripheral lymphocyte count defines the clinical phenotypes and prognosis in patients with anti-MDA5-positive dermatomyositis. J Intern Med. 2023; 293(4): 494-507.

[20] RuscittiP, Di Cola I, Di MuzioC, et al. Expanding the spectrum of the hyperferritinemic syndrome, from pathogenic mechanisms to clinical observations, and therapeutic implications. Autoimmun Rev. 2022; 21(7): 103114.

[21] RenX, WenW, FanX, et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell. 2021; 184(7): 1895-1913.e19. doi:10.1016/j.cell.2021.01.053

[22] NiuQ, ZhaoLQ, MaWL, et al. A new predictive model for the prognosis of MDA5(+) DM-ILD. Frontiers in medicine. 2022; 9: 908365.

[23] AyaubEA, PoliS, NgJ, et al. Single Cell RNA-seq and mass cytometry reveals a novel and a targetable population of macrophages in idiopathic pulmonary fibrosis. 2021. doi:10.1101/2021.01.04.425268 bioRxiv

[24] JoshiN, Watanabe S, VermaR, et al. A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages. Eur Respir J. 2020; 55(1).

[25] ReyfmanPA, WalterJM, JoshiN, et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am J Respir Crit Care Med. 2019; 199(12): 1517-1536. doi: 10.1164/rccm.201712-2410OC

[26] MuroY, Sugiura K, HoshinoK, et al. Epidemiologic study of clinically amyopathic dermatomyositis and anti-melanoma differentiation-associated gene 5 antibodies in central Japan. Arthritis Res Ther. 2011; 13(6): R214.

[27] NishinaN, SatoS, MasuiK, et al. Seasonal and residential clustering at disease onset of anti-MDA5-associated interstitial lung disease. RMD Open. 2020; 6(2).

[28] ReymondN, ImbertAM, DevilardE, et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J Exp Med. 2004; 199(10): 1331-41.

[29] NarasimhanPB, Marcovecchio P, HamersAAJ, et al. Nonclassical monocytes in health and disease. Annu Rev Immunol. 2019; 37: 439-456.

[30] LvX, JinY, ZhangD, et al. Low circulating monocytes is in parallel with lymphopenia which predicts poor outcome in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease. Front Med. 2021; 8: 808875.

[31] VegliaF, PeregoM, GabrilovichD. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018; 19(2): 108-119.

[32] LianX, ZouJ, GuoQ, et al. Mortality risk prediction in amyopathic dermatomyositis associated with interstitial lung disease: the FLAIR model. Chest. 2020; 158(4): 1535-1545.

[33] NaraM, Komatsuda A, OmokawaA, et al. Serum interleukin 6 levels as a useful prognostic predictor of clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease. Mod Rheumatol. 2014; 24(4): 633-636.

[34] ShimizuT, KogaT, FurukawaK, et al. IL-15 is a biomarker involved in the development of rapidly progressive interstitial lung disease complicated with polymyositis/dermatomyositis. J Intern Med. 2021; 289(2): 206-220.

[35] NakanoM, FujiiT, HashimotoM, et al. Type I interferon induces CX3CL1 (fractalkine) and CCL5 (RANTES) production in human pulmonary vascular endothelial cells. Clin Exp Immunol. 2012; 170(1): 94-100.

[36] TakadaT, AokiA, AsakawaK, et al. Serum cytokine profiles of patients with interstitial lung disease associated with anti-CADM-140/MDA5 antibody positive amyopathic dermatomyositis. Respir Med. 2015; 109(9): 1174-80.

[37] HeJ, LiuZ, CaoY, et al. Single-cell landscape of peripheral immune response in patients with anti-melanoma differentiation-associated gene 5 dermatomyositis. Rheumatology (Oxford). 2023; doi:10.1093/rheumatology/kead597

[38] CondamineT, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011; 32(1): 19-25.

[39] RodriguezPC, Quiceno DG, OchoaAC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 2007; 109(4): 1568-1573.

[40] De SantoC, SalioM, MasriSH, et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest. 2008; 118(12): 4036-48.

[41] NomanMZ, Desantis G, JanjiB, et al. PD-L1 is a novel direct target of HIF-1α and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014; 211(5): 781-90.

[42] ZhouM, LiM, GuoC, et al. Circulating TFH cells is correlated with disease activity in anti-MDA5 antibody positive idiopathic inflammatory myopathies. Clin Exp Rheumatol. 2021; 39(4): 804-810.

[43] GeY, ChengD, JiaQ, et al. Mechanisms underlying the role of myeloid-derived suppressor cells in clinical diseases: good or bad. Immune Netw. 2021; 21(3): e21.

[44] WuH, ZhenY, MaZ, et al. Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci Transl Med. 2016; 8(331): 331ra40.

[45] LiD, LuL, KongW, et al. C-type lectin receptor Dectin3 deficiency balances the accumulation and function of FoxO1-mediated LOX-1(+) M-MDSCs in relieving lupus-like symptoms. Cell Death Dis. 2021; 12(9): 829.

[46] GuoC, HuF, YiH, et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann Rheum Dis. 2016; 75(1): 278-85.

[47] ZhangH, WangS, HuangY, et al. Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin Immunol. 2015; 157(2): 175-86.

[48] GengZ, MingB, HuS, et al. α-Difluoromethylornithine suppresses inflammatory arthritis by impairing myeloid-derived suppressor cells. Int Immunopharmacol. 2019; 71: 251-258.

[49] GuhaP, Gardell J, RabinowitzB, et al. Monocytic and granulocytic myeloid-derived suppressor cell plasticity and differentiation are organ-specific. Oncogene. 2021; 40(3): 693-704.

[50] NyweningTM, Wang-Gillam A, SanfordDE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016; 17(5): 651-62.

[51] XieM, LinZ, JiX, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol. 2023; 79(1): 109-125.

[52] LawrenceT, NatoliG. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011; 11(11): 750-761.

[53] HuX, LiJ, FuM, et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1): 402.

[54] SoH, SoJ, LamTT, et al. Seasonal effect on disease onset and presentation in anti-MDA5 positive dermatomyositis. Frontiers in medicine. 2022; 9: 837024.

[55] ToquetS, Granger B, UzunhanY, et al. The seasonality of Dermatomyositis associated with anti-MDA5 antibody: An argument for a respiratory viral trigger. Autoimmun Rev. 2021; 20(4): 102788.

[56] TonuttiA, MottaF, CeribelliA, et al. Anti-MDA5 antibody linking COVID-19, type I interferon, and autoimmunity: a case report and systematic literature review. Front Immunol. 2022; 13: 937667.

[57] KitajimaT, Funauchi A, NakajimaT, et al. Antimelanoma differentiation-associated gene 5 antibody-positive interstitial lung disease after vaccination with COVID-19 mRNA vaccines. J Rheumatol. 2022; 49(10): 1158-1162.

[58] LiaoM, LiuY, YuanJ, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020; 26(6): 842-844.

[59] Schulte-SchreppingJ, Reusch N, PaclikD, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020; 182(6): 1419-1440.e23. doi:10.1016/j.cell.2020.08.001

[60] Giamarellos-BourboulisEJ, NeteaMG, RovinaN, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020; 27(6): 992-1000.e3.

[61] XuG, QiF, LiH, et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov. 2020; 6(1).

[62] XuL, YouH, WangL, et al. Identification of three different phenotypes in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis patients: implications for prediction of rapidly progressive interstitial lung disease. Arthritis Rheumatol. 2023; 75(4): 609-619.

[63] YangQ, LyuK, LiJ, et al. Anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis exhibit three clinical phenotypes with different prognoses. Clin Exp Rheumatol. 2022; 40(2): 304-308.

[64] LundbergIE, Tjärnlund A, BottaiM, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017; 76(12): 1955-1964. doi:10.1136/annrheumdis-2017-211468

[65] MeyerKC, RaghuG, BaughmanRP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012; 185(9): 1004-14.

[66] MarimuthuR, Francis H, DervishS, et al. Characterization of human monocyte subsets by whole blood flow cytometry analysis. J Vis Exp. 2018;(140) doi:10.3791/57941

[67] StreetK, RissoD, FletcherRB, et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. Bmc Genomics [Electronic Resource]. 2018; 19(1): 477.

[68] MorseC, TabibT, SembratJ, et al. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur Respir J. 2019; 54(2)

[69] WendischD, Dietrich O, MariT, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell. 2021; 184(26): 6243-6261.e27.

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.