Background: Ulcerative colitis (UC) is a chronic multifactorial disease with limited management options. Hyperactivation of Janus kinase (JAK) signaling is implicated in the pathogenesis of UC. Recently, non-selective JAK inhibitors were approved for UC treatment; however, toxicity of non-selective JAK inhibition remains a significant constraint and is likely due to indiscriminate JAK inhibition instead of cell-specific JAK targeting. The mechanisms by which upregulated JAK signaling contributes to the development of UC remain unclear. Under colonic homeostasis, CD90⁺ mesenchymal cells suppress T/NKT cell inflammatory responses. Dysregulation of these suppressive functions promote chronic inflammation in UC. In UC, JAK2 expression/activity is increased within mesenchymal cells known as Inflammatory Fibroblasts (iFibs). However, the mechanistic relevance of increased JAK2 expression in iFibs in UC (UC-iFibs) remains unknown. We hypothesize that increased JAK2 expression and signaling within mesenchymal cells governs their pathologic activity and promotes UC-iFib-mediated dysregulation of type 2/17 immune responses.

Methods: Human UC-derived mesenchymal cells were used in this study. Mesenchymal lineage- and fibroblast-specific conditional JAK2 overexpressing mice (Grem1CreJAK2^VF+/-B6 and Col1αCreJAK2^VF+ respectively) were used in two models of UC relevant colitis (TNBS and WASP KO).

Results: Analysis of publicly available scRNAseq data revealed that JAK2 overexpression in UC-iFib was concomitant with increased expression of UC-relevant pathologic responses (IL-6, IL-33, PD-L1). These responses were abrogated UC-iFibs cultured in presence of a JAK2-specific inhibitor. We observed that induction of JAK2 overexpression within fibroblasts at the initiation of chronic inflammation (~3-month-old Col1αCreJAK2^VF+ WASP KO) aggravated the clinical features of UC relevant WASP KO murine colitis. Similarly, we observed that induction of JAK2 overexpression within mesenchymal lineage cells prior to induction of TNBS colitis exacerbates clinical features of colitis such as increased disruption of colonic architecture and increased UC-iFib linked-inflammatory responses. Importantly, JAK2 overexpression within mesenchymal lineage cells in Grem1CreJAK2^VF+/-B6 mice was sufficient to induce colitis with UC-relevant features including colonic mucosal inflammation and cryptitis, as well as increased type 2 and 17 immune responses.

Conclusions: Overexpression of JAK2 within mesenchymal cells is critical to their pathologic activity and is among the key events contributing to the development of chronic inflammation in UC. Therefore, cell-specific targeting of JAK2 may be a promising approach to overcome current challenges in JAK inhibitor-based UC therapy.

Ashley Seideneck

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