Restored macrophage function ameliorates disease pathophysiology in a mouse model for IL10 receptor deficient very early onset inflammatory bowel disease.

Background and aims Mutations in IL10 or the IL10-receptor lead to very early onset (VEO) inflammatory bowel disease (IBD), a life-threatening disease which is often unresponsive to conventional medication. Recent studies have demonstrated that defective IL-10 receptor signaling in innate immune cells is a key driver of severe intestinal inflammation in VEO-IBD. Specifically, IL10 unresponsiveness of macrophages, which govern the tight balance between pro- and anti-inflammatory responses in the intestinal system, plays a central role in the events leading to excessive inflammatory responses and the development of IBD. Methods and results We here evaluated hematopoietic stem cell gene therapy in a VEO-IBD mouse model and demonstrate that the therapeutic response closely correlates with gene correction of the IL-10 signaling pathway in intestinal macrophages. This finding prompted us to evaluate the therapeutic efficacy of macrophage transplantation in the Il10rb -/- VEO-IBD mouse model. A 6-week regimen employing a combination of depletion of endogenous hyperinflammatory macrophages followed by intraperitoneal administration of wild-type macrophages significantly reduced colitis symptoms. Conclusion In summary, we show that the correction of the IL10 receptor-defect in macrophages either by genetic therapy or transfer of WT macrophages to the peritoneum can ameliorate disease-related symptoms and potentially represent novel treatment approaches for VEO-IBD patients.