Interleukin‐1β–Activated Microvascular Endothelial Cells Promote DC‐SIGN–Positive Alternatively Activated Macrophages as a Mechanism of Skin Fibrosis in Systemic Sclerosis

Abstract

Objective To characterize the role of interleukin‐1β (IL‐1β) and microvascular endothelial cells (MVECs) in the generation of alternatively activated macrophages in the skin, and to explore their role in the development of skin fibrosis in patients with systemic sclerosis (SSc; scleroderma). Methods Conditioned medium prepared with MVECs purified from the skin of healthy donors and the skin of SSc patients was used to generate monocyte‐derived macrophages. Flow cytometry, multiplex protein assessment, real‐time quantitative polymerase chain reaction, and tissue immunofluorescence were used to characterize MVEC‐induced polarization of alternatively activated macrophages. Coculture experiments were conducted to assess the role of MVEC‐induced alternatively activated macrophages in fibroblast activation. Alternatively activated macrophages were characterized in the skin of healthy donors and SSc patients using multiparametric immunofluorescence and multiplex immunostaining for gene expression. Based on our in vitro data, we defined a supervised macrophage gene signature score to assess correlation between the macrophage score and clinical features in patients with SSc, using the Spearman's test. Results IL‐1β–activated MVECs from SSc patients induced monocytes to differentiate into DC‐SIGN+ alternatively activated macrophages producing high levels of CCL18, CCL2, and CXCL8 but low levels of IL‐10. DC‐SIGN+ alternatively activated macrophages showed significant enhancing effects in promoting the production of proinflammatory fibroblasts and were found to be enriched in perivascular regions of the skin of SSc patients who had a high fibrosis severity score. A novel skin transcriptomic macrophage signature, defined from our in vitro findings, correlated with the extent of skin fibrosis (Spearman's r = 0.6, P = 0.0018) and was associated with early disease manifestations and lung involvement in patients with SSc. Conclusion Our findings shed new light on the vicious circle implicating unabated IL‐1β secretion, MVEC activation, and the generation of DC‐SIGN+ alternatively activated macrophages in the development of skin fibrosis in patients with SSc.

Orofacial Complications of the Connective Tissue Disease Systemic Sclerosis

“…IL-1β has a significant role in fibrosis by stimulating collagen deposition and myofibroblast differentiation ( Aden et al 2010 ). Increased IL-1β levels in serum and skin biopsies from SSc patients were positively correlated with fibrotic and inflammatory skin scores ( Lin et al 2019 ; Laurent et al 2022 ). Furthermore, IL-1β has been considered as a key modulator in promoting periodontal tissue destruction ( Fig.…”

New Potentiality of Bioactive Substances: Regulating the NLRP3 Inflammasome in Autoimmune Diseases

“…Upon sustained activation of the NLRP3 inflammasome, high levels of IL-1β in the bloodstream promote the differentiation of monocytes into macrophages through endothelial cell mediation. These macrophages then secrete high levels of pro-fibrotic factors such as CCL18, CCL2, and CXCL8, exacerbating skin fibrosis in SSc patients [172]. Furthermore, altered levels of macrophage migration inhibitory factor (MIF) have been observed in different tissues of localized and diffuse SSc patients [173].…”

Role of NLRP3 inflammasome in systemic sclerosis

“…NLRP3 inflammasome is usually regarded as an inhibitor in M2 activation; however, an increased number of M2 and the activation of NLRP3 inflammasome appear simultaneously in asthma patients [ 69 ]. What is more, research discovered that IL-1β-treated vascular endothelial cells mediated M2 activation in highly fibrotic skin [ 70 ].…”