The synergistic impact of granulocytic myeloid-derived suppressor cells and innate lymphoid cells in systemic sclerosis.

Abstract

Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by immune dysregulation and fibrosis, with myeloid-derived suppressor cells (MDSCs) emerging as important regulators of immune responses. However, the role of MDSCs in SSc-associated fibrosis and their interactions with other immune cell populations remain poorly understood. Peripheral blood (SSc: N=37, healthy: N=27) and skin biopsies (SSc: N=9, healthy: N=5) were analyzed using flow cytometry and fluorescence microscopy, respectively. Bleomycin-induced mouse models of fibrosis were used to validate findings, including pharmacological disruption of granulocytic MDSC (G-MDSC) activity via Bruton's tyrosine kinase inhibition (ibrutinib). Single-cell RNA sequencing data from SSc and control skin and lung samples (skin: 19 SSc, 20 healthy; lung: 7 SSc, 15 healthy), complemented by spatial transcriptomics analysis of skin (12 SSc, 7 healthy), were integrated to define cellular interactions relevant to disease pathogenesis. Functional studies and bulk RNA sequencing were conducted to dissect the underlying G-MDSC interactions. G-MDSCs were significantly enriched in the circulation and skin of SSc patients, correlating with disease severity. Experimental fibrosis revealed enrichment of G-MDSCs, whereas monocytic MDSCs remained stable. Transcriptomic data revealed a strong interaction between MDSCs and type 2 innate lymphoid cells (ILC2s), promoting a pro-fibrotic environment via IL-13-driven TGFβ, Arginase1 and CCL24. Functional assays confirmed that G-MDSCs promote Tgfb1 expression in ILC2s, further driving tissue fibrosis. These findings explore a so far unknown G-MDSC-ILC2 axis as a driver of fibrosis in SSc. Targeting this interaction may represent a novel therapeutic strategy to mitigate fibrotic disease progression.