IL-37b Inhibits Periodontitis in Murine Model

Objectives: Interleukin-37 (IL-37) is an anti-inflammatory cytokine and plays an important role in inflammatory and autoimmune disease. Our genome-wide association studies (GWAS) discovered two IL-37 loci with common (minor allele frequency=30%) missense polymorphisms that were associated with high gingival crevicular fluid (GCF) IL-1β levels and more severe periodontal disease. These findings suggest that IL-37 may play a critical role in maintaining the inflammatory balance during the development of periodontitis. However, little is known about the role of IL-37 in periodontal disease. Mice do not express IL-37 or a homologue, but do express the receptor for IL-37. Thus, this study investigated the effect of exogenous IL-37 on the development of periodontitis using an in vivo murine model.
Methods: First, the dominant IL-37 isoform in human gingival tissues was identified by qPCR using isoform-specific primers and localized by immunohistology. The effects of intraperitoneal recombinant human IL-37b (rHIL-37b) were examined in a murine ligature periodontitis model. The effects on periodontitis-associated alveolar bone loss were evaluated by micro-CT and gingival tissue inflammation was determined by histological analysis. Differences between phosphate buffered saline (PBS) injection and rHIL-37 in pro- and mature forms were tested using ANOVA and a conventional p<0.05 statistical significance threshold.


Results: In human periodontitis tissues among the 5 isoforms of IL-37, IL-37b was the dominant isoform. Mice (n=8/group) treated with rHIL-37b demonstrated significantly less alveolar bone loss and gingival tissue inflammatory cell infiltration.
Conclusions: Our studies provide strong evidence that IL-37b plays an immunosuppressive role in the pathogenesis of periodontitis in vivo by downregulating the infiltration of inflammatory cells and decreasing alveolar bone loss. These results further implicate these IL-37 polymorphisms, if shown to be loss-of-function variants, to predisposition for severe periodontitis. Importantly, our findings highlight a possible new therapeutic strategy involving use of IL-37b to suppress the pathogenesis of periodontal disease.