Microbiota-Induced IL-36[gamma] Promotes IL-22-Producing Neutrophil Accumulation and Resolution of Colonic Damage

• Published in: Digestive diseases and sciences 2022-05, Vol.60 (9), p.2555
• Main Authors: Medina-Contreras, Kyle L. Flannigan Oscar, Harusato, Akihito, Nishio, Hikaru, Ngo, Vu, Leoni, Giovanna, Neumann, Philipp-Alexander, Geem, Duke, Lili, Loukia N, Ramadas, Ravisankar A, Parkos, Charles A, Towne, Jennifer E, Nusrat, Asma, Denning, Timothy L
• Format: Article
• Language: English
• Subjects: Colitis; Gastrointestinal diseases; Microbiota (Symbiotic organisms)
• ISSN: 0163-2116

IL-36[gamma] is a novel IL-1 family member that is preferentially expressed by inflammatory monocytes/macrophages during experimental colitis and human inflammatory bowel disease. Previous in vitro work from our lab demonstrated that IL-36[gamma] is produced by macrophages in response to bacterial ligands and is capable of stimulating the production of the neutrophil chemokines CXCL1 and CXCL2 from intestinal epithelial cells. In the current study we attempted to further examine if this axis was driven by the microbiota in vivo. Using DSS to induce intestinal injury in mice, we found that as there was no increase in IL-36[gamma] expression after the induction of intestinal injury in antibiotic-treated or germ-free mice. Interestingly, the number of infiltrating neutrophils was also decreased in mice that received antibiotics. Therefore, to gain further insight into how the IL-36[gamma]-IL-36R axis promotes the resolution of injury and if this is mediated through intestinal neutrophils we examined injury and healing in IL-36R knockout mice. We found that over the course of DSS-induced injury and healing, IL-36R knockout mice had decreased accumulation of neutrophils into the colon compared to wild type mice and this coincided with decreased levels of mRNA expression of CXCL1 and CXCL2 in the injured colon. Remarkably, the dramatic reduction in neutrophil accumulation in IL-36R KO mice resulted in reduced clinical parameters of inflammation during the damage phase, but impaired resolution of intestinal injury. Further investigation found that these infiltrating neutrophils were an important source of IL-22 and the use an aryl hydrocarbon receptor (AhR) agonist to increase IL-22 production was sufficient to reverse the impaired healing observed in IL-36R knockout mice. Finally we found that the expression of IL-22 was also blunted in antibiotic-treated and germfree mice suggesting this axis of healing is directly linked to the presence of the microbiota. In conclusion, the IL-36[gamma]-IL-36R axis aids in wound healing through a mechanism that is dependent on the microbiota and the production of IL-22 from infiltrating neutrophils, highlighting the need to consider therapies that affect not only inflammation but, also the highly coordinated healing process in the intestine.