Innate Immune IL1β Production is Critical in Mediating Intestinal Inflammation in IL10 Receptor Deficiency in Mice and Humans

Background: IL10 receptor (IL10R) mutations cause severe infantile IBD. We have recently reported that intact IL10R signaling is required for generation and function of anti-inflammatory macrophages (Mφ), and that adoptive transfer of WT CD4⁺ T cells into Il10rb^-/-Rag1^-/- mice leads to severe colitis. Our current objective was to determine the role of Mφ-induced IL1β in mediating the inflammatory process in IL10R deficiency in mice and humans.

Results: LPS-treated bone-marrow derived Mφ from IL10R-deficient mice and monocyte-derived Mφ from four patients with loss of function mutations in IL10R genes produced significantly higher levels of IL1β and caspase-1, compared to Mφ from WT mice and healthy human controls, respectively. Moreover, pre-treatment of these Mφ with IL10 prior to LPS stimulation led to a decrease in IL1β production only in WT murine and human control Mφ, but not in IL10R-deficient murine or patient Mφ. A role for innate immune IL1β in mediating intestinal inflammation was also shown in-vivo, since transfer of Il1r^-/- CD4⁺ T cells, but not WT CD4⁺ T cells, into Il10rb^-/-Rag1^-/- mice led to attenuated colitis. Finally, Anakinra (an IL1 receptor antagonist) treatment of a toddler with severe infantile IBD due to loss of function IL10RA mutation led to a marked clinical, laboratory and histological improvement enabling a significant decrease in steroid dose, prior to stem cell transplantation (SCT). 

Conclusion: Innate immune cell-derived IL1β  is critical in mediating exaggerated pro-inflammatory responses in IL10R deficiency. The value of IL1 neutralization as a therapeutic bridge to SCT in patients with IL10R deficiency warrants further investigation.