W109 - JAK2 Overexpression in Mesenchymal Cells: Role in the Immunopathogenesis of UC

Christina McAninch – Penn State College of Medicine; Marina Chulkina – Penn State College of Medicine; Steven McAninch – Penn State College of Medicine; Rachelle Edwards – Penn State College of Medicine; Ashley Seideneck – Penn State College of Medicine; Walter Koltun – Penn State College of Medicine; Gregory Yochum – Penn State College of Medicine; Irina Pinchuk – Penn State College of Medicine

Abstract Text: Cells of mesenchymal origin, known as fibroblasts and their progenitors, are present in colonic mucosa, serve as immunosuppressors under homeostasis, and are suggested to be among key contributors to the immunopathogenesis of ulcerative colitis (UC). An increase in pathological fibroblasts known as Inflammatory Fibroblasts (UC-iFibs) was observed in UC and these cells expressed high levels of JAK2. While targeting JAK pathways has shown therapeutic promise, the mechanistic relevance of JAK2 upregulation in UC-iFibs remains unknown. We hypothesize that increased JAK2 signaling within UC-iFibs governs their pathological activity and promotes inflammation in UC.

Human UC-derived mesenchymal cells were used in this study. Mesenchymal lineage- and fibroblast-specific conditional JAK2 overexpressing mice (Grem1CreJAK2VF+/- B6 and Col1αCreJAK2VF+ WASPKO respectively) were used in two models of UC-relevant colitis (TNBS and WASP KO).
JAK2high UC-iFib primary human cultures treated with JAK2-specific inhibitor show significantly reduced expression of UC-relevant pathologic responses (IL-6, IL-15, IL-33, PD-L1). In vivo induction of JAK2 overexpression within fibroblasts at the initiation of chronic inflammation in Col1αCreJAK2VF+ WASP KO mice aggravated the clinical and histological features of colitis, and increased UC-relevant type 2 inflammatory responses. Importantly, JAK2 overexpression within mesenchymal lineage cells in Grem1CreJAK2VF+/- B6 mice was sufficient to induce colitis with UC-relevant histological features and increased pathologic type 2/17 responses. Overexpression of JAK2 in mesenchymal cells also aggravated TNBS colitis.

Our data suggests that overexpression of JAK2 within mesenchymal cells is critical to the pathological activity of UC-iFib and is among the key events contributing to the development of UC.