The Contribution of CD40/CD40L Axis in Inflammatory Bowel Disease: An Update

Abstract

Inflammatory bowel disease (IBD) is a chronic and multifactorial disease of the gastrointestinal tract. The exact etiology of IBD remains complex and unclear involving an inadequately defined relationship between microbial insult, genetic predisposition, altered intestinal barrier permeability, oxidative stress components and abnormal immune responses. The role of the co-stimulatory system made up of cluster of differentiation 40 protein (CD40) and its ligand (CD40L) in the response of the immune system to pathogens is now widely accepted. The implication of CD40/CD40L axis in immune system disorders due to its important role as signal transduction pathway among immune cells is well documented. Several studies have suggested that CD40/CD40L interactions regulate oxidative stress; this can affect various signaling pathways leading to IBD development. Hence, CD40/CD40L signaling pathway may become a new target for IBD treatment. This review will cover the general contribution of the CD40/CD40L dyad in the development of IBD in order to facilitate future approaches aiming to elucidate the immunological mechanisms that control gut inflammation.

Keywords: CD40; CD40L; immunity; inflammatory bowel disease; signaling pathways.

Figure 1

CD40/CD40L axis in activated dendritic cells. CD40/CD40L axis is implicated in many downstream pathways in activated dendritic cells that are essential for its function. CD40L induces the activation of dendritic cells through its binding to CD40. This activation requires the recruitment of the TRAFs family. This leads in turn to the activation of several pathways, such as STAT3, NF-κB, and MKKs. They are all mostly involved in many gene expressions that include cell survival, cell adhesion as well as procoagulant activity and pro-inflammatory cytokines production. On the other side, other pathways that go through different receptors influence DC activity, among them TNF-α inducing mostly an pro-atherogenic activity or IL-10 receptor that can enhance an opposite function and therefore promote an anti-atherogenic activity in DC.

Figure 2

CD40/CD40L in IBD. CD40/CD40L axis contributes to the activation of various pathways related to inflammation in immune and non-immune cells, hence promoting IBD. In the early stages of mucosal inflammation, local T cells become activated and express CD40L, binding to and activating CD40⁺ DC. Therefore, CD40⁺ DC enhances cytokine secretion, such as IL-12, and up-regulation of co-stimulatory activity including CD40, CD40L, and MHC-II activity promoting more T cells that transmigrate into the interstitial space become activated with expressed CD40L. Activated T cells in the circulation of patients with IBD contribute to this process through expression of CD40L on their surface.