Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by persistent intestinal inflammation, a dysregulated immune response to the microbiota, and impairment of the epithelial barrier. Their incidence and prevalence continue to rise worldwide, while current treatments—anti-inflammatory drugs, corticosteroids, immunosuppressants, or biological agents targeting TNFα or the α4β7 integrin—fail to induce remission in more than half of patients, and relapses as well as fibrotic complications occur frequently. These limitations stem from the fact that such approaches aim to prevent or attenuate inflammation, without acting on its chronicity or restoring tissue homeostasis. Yet the resolution of inflammation is an active process, governed in particular by specialized pro-resolving lipid mediators (SPMs) that activate G protein-coupled receptors to trigger neutrophil apoptosis, limit their tissue recruitment, and promote efferocytosis by macrophages.
Using transcriptional analyses conducted in up to 300 patients with IBD, the authors identified potential therapeutic targets implicated in chronic inflammation. They show that ChemR23, a G protein-coupled receptor targeted by resolvin E1 (RvE1), is overexpressed in the inflamed colonic tissues of patients with severe forms refractory to both anti-TNFα and anti-α4β7 therapies, this overexpression being associated with a substantial mucosal accumulation of neutrophils. This observation suggests that the failure of current treatments could be linked to neutrophilic infiltration.
The team then characterized an agonist anti-ChemR23 monoclonal antibody, capable of inducing receptor signaling, promoting macrophage efferocytosis, and reducing neutrophil apoptosis at the site of inflammation. The efficacy of this antibody was evaluated in several murine models of colitis, both acute and chronic (DSS induction, TNBS induction, adoptive transfer of CD4+ T cells into Rag1KO mice, IL-10-deficient mice), as well as in colorectal tumor models, including the azoxymethane-DSS model. Unlike RvE1, whose limited bioavailability and rapid clearance restrict its use to models of spontaneously resolving acute inflammation, the antibody accelerated the resolution of acute inflammation and triggered resolution in already-established, non-spontaneously resolving chronic colitis.
This resolution was accompanied by a significant reduction in tissue damage, fibrosis, and inflammation-induced tumors. This work designates ChemR23 as a promising therapeutic target for the treatment of chronic inflammation and provides support for the role of neutrophilic infiltration in resistance to current IBD therapies.