Background/Purpose:  Type 2 innate lymphoid cells (ILC2s) are identified as population of cells with lymphoid morphology lacking re-arranged antigen-specific receptors. Recently, emerging data show that ILC2s might play a key role in the pathogenic process of fibrotic diseases. However, the potential benefit of applying ILC2s as therapeutic target remains to be elucidated. We aimed to profile ILC2s in fibrotic tissues and to evaluate the functional impact of IC2s in the pathogenesis of systemic sclerosis (SSc).

Methods:  Human blood samples and skin sections (sixty-nine patients with SSc and 47 healthy controls) as well as skin and lung tissue of various fibrotic mouse models were analyzed by flow cytometry and multi-color immunohistochemistry using several complementary panels of markers each. Kinetics of ILC2 accumulation during the course of fibrosis was studied and ILC2s were further profiled by transcriptome as well as secretome analysis.

Results:  Significantly elevated numbers of ILC2s were detected in the skin (10-fold increase) and blood (4-fold increase) of SSc patients by two independent established sets of ILC2 markers compared to healthy controls. In contrast to circulating ILC2s, skin-resident ILC2s express various activation markers and stained positive for skin homing markers. Furthermore, our data suggest that ILC2s might be involved in the pathogenesis of fibrosis in SSc by showing multiple associations of ILC2 counts with fibrotic manifestations in SSc patients. Significantly higher frequencies were observed in diffuse cutaneous (dc)SSc patients compared to limited cutaneous SSc (lcSSc). The modified Rodnan Skin Score (mRSS) positively correlated with ILC2 counts and pulmonary involvement. In parallel, we detected significantly elevated numbers of ILC2s in the fibrotic skin of bleomycin-induced and DNA topoisomerase I-induced mice compared to control mice. Moreover, in the tight-skin (Tsk)-1model of fibrosis resembling less inflammatory stages of SSc significantly increased ILC2 counts were detected compared to control mice. Kinetic analyses revealed an early upregulation of ILC2s in experimental models of fibrosis. In contrast to lineage positive lymphocytes that peak at early inflammatory stages of fibrosis, however disappear over time, ILC2s persist also in later stages of established fibrosis. Profiling of ILC2s in the fibrotic tissue revealed exaggerated production of pro-fibrotic cytokines that in turn activate fibroblasts to produce extracellular matrix proteins.

Conclusion:  Here, we provide first evidence for a role of ILC2s in the pathogenesis of SSc by demonstrating increased ILC2 counts in the skin and blood of human SSc patients. These findings were indirectly supported by elevated numbers of ILC2s in the fibrotic skin and lung sections of various mouse models for SSc, reflecting different pathophysiological aspects of the disease. The pro-fibrotic phenotype of ILC2s and their persistant upregulation in early as well as in late stages of fibrosis suggest a central role of ILC2s in the pathogenesis of fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-2-innate-lymphoid-cells-cellular-source-of-profibrotic-mediators-rapidly-and-persistently-recruited-in-experimental-fibrosis-and-systemic-sclerosis/