Targeting activated IL-23 signaling in Scleroderma by tildrakizumab

ABSTRACT The pathogenesis of systemic sclerosis (SSc) involves immune system dysregulation and progressive multi-organ fibrosis. Aberrant interleukin-23 (IL-23) function is linked to many inflammatory conditions. Tildrakizumab, a humanized monoclonal antibody that binds to the p19 subunit of IL-23 to block its interaction with the IL-23 receptor, is FDA-approved for treating psoriasis. IL-23 levels are increased in SSc patients with lung involvement, but the pathogenic role of IL-23 in SSc fibrosis remains unclear. We examined IL-23 expression in SSc skin biopsies and assessed the effects of IL-23 inhibition in an in vivo fibrosis model. We found increased IL-23 expression in SSc compared to healthy skin biopsies. Pharmacological blockade of IL-23 signaling using tildrakizumab reversed experimental skin and lung fibrosis. Our findings support a pathogenic role of IL-23 in SSc and suggest that tildrakizumab could be a novel antifibrotic treatment strategy for SSc and related fibrotic disorders. Graphical abstract