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

OBJECTIVE: Innate 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). METHODS: Blood 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. RESULTS: We 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-ß (TGFß), 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. TGFß-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. CONCLUSION: Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFß and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.

Decreased CCN3 in Systemic Sclerosis Endothelial Cells Contributes to Impaired Angiogenesis.

Systemic sclerosis (SSc) is a rare and severe connective tissue disease combining autoimmune and vasculopathy features, ultimately leading to organ fibrosis. Impaired angiogenesis is an often silent and life-threatening complication of the disease. We hypothesize that CCN3, a member of the CCN family of extracellular matrix proteins, which is an antagonist of the profibrotic protein CCN2 as well as a proangiogenic factor, is implicated in SSc pathophysiology. We performed skin biopsies on 26 patients with SSc, both in fibrotic and nonfibrotic areas for 17 patients, and collected 18 healthy control skin specimens for immunohistochemistry and cell culture. Histological analysis of nonfibrotic and fibrotic SSc skin shows a systemic decrease of papillary dermis surface as well as disappearance of capillaries. CCN3 expression is systematically decreased in the dermis of patients with SSc compared with healthy controls, particularly in dermal blood vessels. Moreover, CCN3 is decreased in vitro in endothelial cells from patients with SSc. We show that CCN3 is essential for endothelial cell migration and angiogenesis in vitro. In conclusion, CCN3 may represent a promising therapeutic target for patients with SSc presenting with vascular involvement.

Association of skin hyperpigmentation disorders with digital ulcers in systemic sclerosis: Analysis of a cohort of 239 patients.

BACKGROUND: Skin pigmentation disorders in systemic sclerosis (SSc) have been sparsely described in the literature. Nevertheless, they could be a diagnostic and/or severity marker. OBJECTIVES: To assess the association between pigmentation disorders and systemic involvement in patients with SSc. METHODS: A total of 5 patterns of skin pigmentation disorders were defined: diffuse hyperpigmentation; hyperpigmentation of sun-exposed areas; hypopigmentation of the head, neck, and/or upper part of the chest; acral hypopigmentation; and diffuse hypopigmentation. RESULTS: A total of 239 patients were included; 88 patients (36.8%) had skin pigmentation disorders as follows: diffuse hyperpigmentation and hyperpigmentation of sun-exposed areas in 38.6% (n = 34) and 27.3% (n = 24) of patients, respectively; hypopigmentation of the face, neck, and/or chest in 10.2% of patients (n = 9); diffuse hypopigmentation in 12.5% (n = 11); and acral hypopigmentation in 17% (n = 15). Diffuse hyperpigmentation was associated with diffuse SSc (P = .001), increased modified Rodnan skin score (P = .001), and shorter duration of Raynaud phenomenon (P = .002) in univariate analysis but not in multivariate analysis. Moreover, diffuse hyperpigmentation was associated with digital ulcers (P = .005), as confirmed by multivariate analysis (odds ratio, 2.96; 95% confidence interval, 1.28-6.89). LIMITATIONS: This was a single-center retrospective study of a cohort of patients with SSc. CONCLUSION: Screening for skin pigmentation disorders could be useful in the management of patients with SSc to identify those with a high risk of development of digital ulcers, which is a symptom of vascular involvement in SSc.

Immune-Mediated Repair: A Matter of Plasticity.

Though the immune system is generally defined as a system of defense, it is increasingly recognized that the immune system also plays a crucial role in tissue repair and its potential dysregulations. In this review, we explore how distinct immune cell types are involved in tissue repair and how they interact in a process that is tightly regulated both spatially and temporally. We insist on the concept of immune cell plasticity which, in recent years, has proved fundamental for the success/understanding of the repair process. Overall, the perspective presented here suggests that the immune system plays a central role in the physiological robustness of the organism, and that cell plasticity contributes to the realization of this robustness.