RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

Abstract

Clostridium difficile (C. difficile) infection results in toxin-induced epithelial injury and marked colonic inflammation. Mitogen-activated protein kinase (MAPK) and NF-jB which regulated by MAP kinase phosphatase (MKP, also known as dual specificity phosphatases, DUSP) are fundamental signalling pathways that mediate multiple cellular processes. However, the regulation of DUSP/MAPKs and NF-jB pathway in C. difficile-induced colonic inflammation remains unclear. Here, we report that TcdB significantly inhibits cell viability and induces production of IL-1b and TNF-a and activation of MAPKs and NF-jB. An E3-ubiquitin ligase, TRIM46, ubiquitinates DUSP1, and its knockdown significantly inhibit TcdB-induced activation of MAPKs and NF-jB and production of IL-1b and TNF-a. Moreover, TRIM46 overexpression induced production of IL-1b and TNF-a also reversed by DUSP1 overexpression. We further found that promoter of TRIM46 also demonstrated binding to NF-jBp65, leading to regulate TRIM46 expression. In addition, the increased colonic inflammation induced by C. difficile administration was inhibited by TRIM46 knockdown in vivo. Taken together, the present study shows that TRIM46, as a new regulator of DUSP1/MAPKs and NF-jB signalling pathway, plays an important role in TcdBinduced colonic inflammation.

Pathobionts: mechanisms of survival, expansion, and interaction with host with a focus on Clostridioides difficile

“…Li et al . 77 also showed that these effects were mediated by binding of the TRIM46 to the promoter region of the NF-κBp65 subunit. In addition to pro-inflammatory mediators in acute colitis of CDI, inflammation was further accompanied by infiltration of immune cells.…”

“…Li et al . 77 reported the role of a MAP kinase phosphatase DUSP1 on inhibition of the MAPK activity. A knockout mutant of TRIM46, which ubiquitinates DUSP1, could inhibit TcdB-induced MAPK and NF-κB signaling, leading to the repression of TNF-α and IL-1β.…”

“…Furthermore, the mutant inhibited the increased colonic inflammation induced by CDI. 77 Additionally, the overexpression of the E3-ubiquitin ligase TRIM46 induced elevated levels of proinflammatory cytokines TNF-α and IL-1β. Li et al .…”

Proinflammatory Cytokines: Possible Accomplices for the Systemic Effects of Clostridioides difficile Toxin B

“…(a) The production of high levels of proinflammatory cytokines is necessary. [17][18][19][20][21][44][45][46][47][48] In patients with severe CDI, the systemic inflammatory response (as documented in both patients and experimental animal models) 6,10-13,48,51 is due to not only local tissue damage but also the inflammatory action of the Tcds, [17][18][19][20][21][44][45][46][47][48]52 the structural and metabolic components released by C. difficile itself, and the modification of the intestinal microbial flora following C. difficile-specific therapy; 5,23-26,53-56 (b) Tcds have to reach the systemic circulation (a characteristic limited to only some patients with CDI). [6][7][8][9][10][11][12][13] In these conditions, the interaction between TcdB, TNF-α and IFN-γ can trigger an increase in the toxicity of TcdB and its systemic pathological effects (Figure 2).…”

Trim46 contributes to the midbrain development via Sonic Hedgehog signaling pathway in zebrafish embryos

“…TRIM46 has been known to be involved in inflammatory response through ubiquitination. It ubiquitinates DUSP1 (Dual-specificity phosphatase 1), which in turn induces activation of NF-κB and MAPK (Mitogen-activated protein kinases) in colonic inflammation (Li et al 2020). On the other hand, TRIM46 acts as an oncogene in osteosarcoma by interacting with and ubiquitinating peroxisome proliferator-activated receptor alpha (PPARα), resulting in the activation of the NF-κB signaling pathway (Jiang et al 2020).…”