INTESTINAL EPITHELIAL-DERIVED IL-34 REGULATES MACROPHAGE POLARIZATION AND GASTROINTESTINAL TRACT GRAFT VERSUS HOST DISEASE

Gastrointestinal (GI) tract graft versus host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remains a major goal in this disease. Herein, we have identified interleukin 34 (IL-34) as a tissue-intrinsic regulatory cytokine that is able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages towards a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ GM-CSF+ T cells within the colon. Conversely, the administration of recombinant IL-34 significantly reduced GVHD mortality and inflammation in the GI tract which was dependent upon the expression of apolipoprotein E (ApoE) in donor macrophages. Complementary genetic and imaging approaches demonstrated that intestinal epithelial cells were the biologically relevant source of IL-34. Colonic biopsies from patients with GVHD also revealed expression of IL-34 in intestinal epithelial cells, as well as ApoE in lamina propria macrophages, validating similar cellular localization in humans. Thus, these studies define IL-34 as an intestinal epithelial-derived cytokine that regulates macrophage polarization in an ApoE-dependent manner, positioning this cytokine as a key regulator of GVHD in the GI tract and a potential therapeutic target for amelioration of this disease.