Soquelitinib inhibition of IL-2-inducible T cell kinase ameliorates lung damage in murine models of systemic sclerosis

Interleukin-2-inducible T cell kinase (ITK) is a tyrosine kinase involved in T cell activation, differentiation, and receptor signaling. Soquelitinib (SQL) is a selective, covalent inhibitor of ITK. The abnormal activation of T cells plays a key role in the early inflammatory stages of systemic sclerosis (SSc). In the study reported here, we investigated the efficacy of SQL in two mouse models of lung fibrosis, and related pulmonary arterial hypertension (PAH), mimicking lung involvement in SSc. SQL was evaluated in the bleomycin-induced lung fibrosis mouse model and the Fra-2 mouse model, characterized by interstitial lung disease (ILD) and pulmonary vascular remodeling leading to PAH. In the bleomycin-induced lung fibrosis model, SQL significantly reduced leucocyte infiltration into the lungs and attenuated interstitial lung damage, primarily by modulating Th2 and Th17 pathways, although it did not affect collagen deposits. In the Fra-2 model, SQL improved clinical scores, reduced histological scores of interstitial lung damage and inflammatory infiltrates, and significantly downregulated Th17-dependent RORγt and STAT3 expression in lesional lungs. While SQL showed a trend toward improved lung function on imaging and modest effects on collagen deposits, it significantly reduced PAH in the Fra-2 mice, improving key cardiac hemodynamic parameters and showing trends of beneficial effects on vascular remodeling. Our findings highlight the potential of selective ITK inhibition with SQL as a promising therapeutic strategy for lung damage and pulmonary vascular remodeling in SSc.