Intestinal myofibroblast-specific Tpl2-Cox-2-PGE ₂ pathway links innate sensing to epithelial homeostasis

Abstract

Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E 2 (PGE 2 ) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE 2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE 2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.Crohn's disease | ulcerative colitis | mesenchymal cells | MAP kinases | cyclooxygenase-2

The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions

“…The secretion of PGE2 by adipocytes was also reduced in these experimental conditions. Thus, our data indicate that Tpl2 in adipocytes is a positive regulator of COX-2 expression and PGE2 production as previously shown in macrophages, T cells and intestinal myofibroblasts (35,39,46). By contrast, in other cellular contexts Tpl2 negatively regulates COX-2 expression and PGE2 production (37).…”

Map3k8 Modulates Monocyte State and Atherogenesis in ApoE −/− Mice

“…20,21 Map3k8 plays a unique role in the production of inflammatory mediators in vivo, 14,19,22 modifying the activation state of macrophages, monocytes, astrocytes, dendritic cells, stellate cells, myofibroblasts, and plasma cells, and no other protein can replace Map3k8 in this role. 16,18,[23][24][25][26][27][28][29] We show here that, in atherogenic conditions, Map3k8 is required to maintain the number of monocytes, by limiting apoptosis. Furthermore, the strong expression of CCR2 on Ly6C high monocytes and the firm adhesion of leukocytes to arterioles and venules in vivo are dependent on Map3k8.…”

ATPL2 (MAP3K8)disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion

“…In contrast, TPL2 in myofibroblasts protects from epithelial injury-induced colitis. 44 Therefore, given the distinct role of TPL2 in different cell types during various forms of intestinal inflammation, it will be important to clearly dissect the outcomes of TPL2 signalling in a variety of IBD-relevant cell types.…”