Sterile triggers drive joint inflammation in TNF‐ and IL ‐1β‐dependent mouse arthritis models

Abstract

Arthritis is the most common extra‐intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed “the gut‐joint‐axis.” The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data, however, support a correlative relationship between gut and joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF‐ or IL‐1β dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full‐blown articular inflammation under germ‐free conditions. In contrast, TNF‐driven gut inflammation is fully rescued in germ‐free conditions, indicating that the microbiota is driving TNF‐induced gut inflammation. Together, our study demonstrates that although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues. image Intestinal and joint inflammation often coincide, and both conditions are associated with dysbiosis of the intestinal microbiota. These findings have fueled the dogma that microbial signals and intestinal inflammation play an indispensable role in initiating and/or perpetuating joint inflammation. To investigate this gut‐joint axis more comprehensively, we made use of transgenic mouse models and germ‐free technology. A new transgenic mouse model of TNF‐driven inflammation was generated using CRISPR/Cas9 technology: TNF emARE mice. Colonized homozygous TNF emARE/ARE mice develop spontaneous axial and peripheral joint inflammation and intestinal inflammation in the ileum. Germ‐free TNF emARE/ARE mice are fully protected from intestinal inflammation but still develop musculoskeletal pathology. A20 myel‐KO mice develop IL‐1β‐driven arthritis without intestinal inflammation in both colonized and germ‐free conditions.