Combined administration of SHP2 inhibitor SHP099 and the α7nAChR agonist PNU282987 protect mice against DSS-induced colitis

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory condition with complex pathogenesis that currently has no cure . α7 nicotinic acetylcholine receptor (α7nAChR) is known to regulate multiple aspects of immune function. The present study aimed to evaluate the protective effects of PNU282987 and SHP099, which are a selective agonist of α7nAChR and an SHP2 inhibitor, respectively, in dextran sulfate sodium (DSS)-induced colitis in mice. Acute colitis was induced in mice using 3% DSS, and weight loss, colonic histology and cytokine production from colonic lamina propria were analyzed to evaluate disease severity. Bone marrow-derived macrophages were treated with lipopolysaccharide (LPS) to induce an inflammatory response. Cytokine expression and reactive oxygen species (ROS) levels were quantified. The α7nAChR agonist, PNU282987, and the SHP2 inhibitor, SHP099, were administered alone or in combination to LPS-induced macrophages or to colitic model mice to evaluate the inflammatory response and protective efficacy in colitis. α7nAChR protein levels were found to be markedly increased in the colon of DSS-induced colitic mice, and were found to co-localize with macrophages. Consistently, α7nAChR mRNA and protein levels were upregulated with colitis progression in DSS-induced colitic mice. Colonic inflammation was attenuated by PNU282987 treatment in DSS-induced mice, as evidenced by reduced weight loss and alleviated colonic epithelial cell disruption. These effects of PNU282987 on colitis were enhanced when it was combined with SHP099. Cytokine production and ROS levels induced by LPS in macrophages were decreased by a combination treatment of PNU282987 and SHP099. These findings identified α7nAChR as an essential element in the role of intestinal macrophages in colonic repair and demonstrated a synergistic effect of PNU282987 and SHP099, suggesting a new potential therapy for IBD.