TNFR1-induced lethal inflammation is mediated by goblet and Paneth cell dysfunction

Abstract

Tumor necrosis factor (TNF) is a powerful activator of the immune system and a well-validated target for treatment of autoimmune diseases. Injection of TNF induces systemic lethal inflammation characterized by hypothermia, induction of multiple cytokines, and extensive damage to multiple organs. Previously, we reported that TNF-induced lethal inflammation is strictly TNFR1(P55)-dependent. We also uncovered a crucial role for P55 expression levels in intestinal epithelial cells (IECs), in which P55+/+ expression is sufficient to sensitize to TNF lethality in an otherwise fully protected P55+/- background. Here, we investigated the molecular mechanism that drives TNF toxicity in IECs. Unexpectedly, we found that the degree of TNF-induced enterocyte damage and apoptosis in IECs is equally strong in TNF-sensitive P55+/+ mice and TNF-resistant P55+/- mice. Our results suggest that P55+/+-induced signaling causes goblet and Paneth cell dysfunction, leading to severe epithelial barrier dysfunction. As a result, intestinal permeability and systemic bacterial spread are induced, causing lethal systemic inflammation. In conclusion, we identified P55-induced goblet and Paneth cell dysfunction as a crucial mechanism for TNF-induced systemic and lethal inflammation.

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

“…Hepatic microvascular dysfunction, 5 leukocyte accumulation and mediated oxidative stress in nonperfused sinusoids, leukocyte-endothelial cell adhesion, 34 and excessive inflammation 35 are important determinants of liver dysfunction induced by intestinal I/R. Since intestinal leakage could disseminate the gut microflora systemically, activate TLR signaling, and amplify inflammatory cytokine production, 36 the integrity of the gut barrier is essential to prevent the microbiota of a healthy individual from triggering bacteria-derived endotoxemia. 37 In this rat model, intestinal I/R caused the breakdown of the mucosa barrier, as shown in histological HE staining, with an association of increased levels of i-FABP and DAO.…”

Yeast fermentate prebiotic improves intestinal barrier integrity during heat stress by modulation of the gut microbiota in rats

“…Depletion of these cells may lead to the development of an epithelial barrier defect (Estienne et al, 2010). Reduction of Paneth and goblet cells was shown to increase sensitivity of mice to TNF-induced toxicity, accompanied by increased hypothermia, lethality and intestinal permeability (Van Hauwermeiren et al, 2015). Decrease of these cells was induced by different stress conditions, such as neonatal maternal separation (Bessette et al, 2016), chronic and heat stress (Deng et al, 2012;Gao et al, 2018).…”

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

“…The genes include LRRK2 and the candidate genes listed in Table 2 and Supplemental Table 4 (4,6,45). TNF-α has also been implicated in the homeostasis of Paneth cell function (46)(47)(48)(49). Therefore, the candidate genes for Paneth cell dysfunction in Japanese CD patients potentially act through modulating autophagy and TNF-α signaling.…”