TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis

Abstract

ObjectiveInnate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc).MethodsBlood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc.ResultsWe found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1− ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-β (TGFβ), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFβ-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis.ConclusionOur results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFβ and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.

Innate Lymphoid Cells in Autoimmune Diseases

“…This population is activated by TGF-b and produces lower levels of IL-10 compared with KLRG1 high ILC2. These KLRG1 low ILC2 cells fail to negatively regulate collagen production by dermal fibroblast, a process which is physiologically IL-10 dependent, thus enhancing skin fibrosis (35). Despite these interesting findings on the role of ILC1 and ILC2 in Ssc pathogenesis and fibrosis development, data are still missing to fully understand the importance of ILC in the pathogenesis of Ssc.…”

“…In humans, ILC1 are mainly found in the tonsils, gut, lung, liver, adipose tissue, skin, lymph nodes, and spleen (4,9,20,40). They show significant differences in the Increased in SSc and RA (33)(34)(35), Decreased in AAV and SLE (27)(28)(29)31) Increased (29) or decreased (27,28) in SLE, Increased (36) or decreased (33) in RA Decreased in AAV (31) Decreased in RA (32) expression of surface markers and transcription factors linked to the microenvironment of the tissue they populate (20). ILC2, like Th2 cells, produce high levels of interleukin (IL)-4, IL-5, and IL-13 in response to epithelial cell-derived IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) (1,10,41).…”

Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis

“…Downregulation of IL-10 increased the production of collagen by dermal fibroblasts. In the same study, TGF-β inhibition combined with IL-10 administration prevented fibrotic manifestations in a mouse model recapitulating SSc [ 49 ]. Although there is a limited number of studies associating ILC2s in the pathogenesis of SSc, we believe that findings implicating TGF-β in their potential fibrotic mechanism might be promising in utilizing alternative therapeutic strategies that are based on TGF-β blocking.…”

Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

“…Additionally, chemokine receptors and integrins expressed at the transcriptional or protein level on mouse/human ILC have been identified. These include the chemokine receptors Ccr2 , Ccr4 /CCR4, CCR6 /CCR6, CCR7 /CCR7, CCR8, CCR9, CCR10, CXCR4 , CXCR3 and CXCR5 CXCR6 /CXCR6, the integrins Icam1 , ITGB2 , ITGAM , ITGAL , ICAM3 , α4β7, αLβ2, α4β1 and S1PR1 and the selectins cutaneous lymphocyte antigen (CLA) or SELL /CD62L [ 34 , 42 , 49 , 58 , 61 , 62 , 63 , 77 , 83 , 84 ]. These observations further highlight that specific patterns of chemokine receptors, integrins and selectins expression enable mouse and human ILC to appropriately traffic within and between tissues to mediate their effector function [ 61 , 83 ].…”