PAM3 protects against DSS-induced colitis by altering the M2:M1 ratio

Begum H Horuluoglu,Dennis Klinman,Debra Tross,Neslihan Kayraklioglu

doi:10.1038/s41598-020-63143-z

Abstract

Inflammation of the gastrointestinal tract contributes to the development of inflammatory bowel disease (IBD). Human IBD is modeled by administering dextran sulfate sodium (DSS) to mice. In humans and mice, inflammatory M1 macrophages contribute to the progression of IBD whereas immunosuppressive M2 macrophages protect against colitis. The TLR2/1 agonist PAM3CSK4 (PAM3) induces human and murine monocytes to differentiate into immunosuppressive M2 macrophages, suggesting that PAM3 might be of benefit in the prevention/treatment of colitis. PAM3 was therefore administered to mice treated with DSS. As hypothesized, the number of M2 macrophages rose and disease severity decreased. The critical role of M2 macrophages in this process was established by transferring purified M2 macrophages from PAM3 treated control donors into DSS recipients and reducing colitis. These findings suggest that PAM3 may represent a novel approach to the treatment of human IBD.

Highlights

Ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the gastrointestinal tract[1]
This work establishes that the TLR2/1 agonist PAM3 significantly reduces the severity of dextran sulfate sodium (DSS) induced colitis
This beneficial effect of PAM3 arose from its ability to generate M2 macrophages, which when transferred from untreated control donors into DSS treated recipients had the same protective effect as PAM3 alone (Fig. 5)

Summary

Introduction

Ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the gastrointestinal tract[1] In both types of IBD, activation of the innate rather than adaptive immune system is critical, with macrophages and dendritic cells contributing to the induction of inflammation[2,3,4,5]. Intestinal macrophages occupy the interface between the host’s GI tract and the resident microbiome These macrophages can contribute to IBD pathogenesis by failing to eliminate inflammation-inducing microbes and/or failing to support the resolution of inflammation that arises via other mechanisms[6]. The murine M2 macrophages co-expressed CD206 and F480 Purified cells of this phenotype were functionally M2 (based on their production of IL-10, phagocytic activity, and inability to produce inflammatory cytokines)[10]. As PAM3 has the same effect on primate as murine monocytes, these findings suggest that the PAM3-based therapy may be of use in the treatment of human colitis

Methods

Results

Conclusion