Intestinal epithelium–derived IL-34 reprograms macrophages to mitigate gastrointestinal tract graft-versus-host disease

• DOI: 10.1126/scitranslmed.adn3963
• Publication Date: 2025-02-12T18:59:31Z
• Authors: Aditya Rayasam; Alison Moe; Matthew Kudek; Ravi K. Shah; Cheng-Yin Yuan; James M. Miller; Mary Rau; Mollie Patton; Karolyn Wanat; Marco Colonna; Anthony E. Zamora; William R. Drobyski
• Keywords: Proinflammatory cytokine; Intestinal epithelium; Lamina propria

Gastrointestinal (GI) tract graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation and attributable to dysregulation that occurs between the effector regulatory arms of immune system. Whereas T cells have primary role in counterbalancing GVHD-induced inflammation, identifying harnessing other pathways promote tolerance remain goals this disease. Herein, we identified interleukin-34 (IL-34) as an intestinal epithelium–derived cytokine was able mitigate severity GVHD within GI tract. Specifically, observed absence recipient IL-34 production exacerbated lethality, promoted epithelial death, compromised barrier integrity. Mechanistically, host skewed donor macrophages toward proinflammatory phenotype augmented accumulation pathogenic CD4 + granulocyte-macrophage colony-stimulating factor (GM-CSF) colon. Conversely, administration recombinant substantially reduced mortality which dependent on expression apolipoprotein E macrophages. Complementary genetic imaging approaches mice demonstrated were relevant source IL-34. These results supported by colonic biopsies from patients with GVHD, displayed lamina propria macrophages, validating similar cellular localization humans. studies indicate acts tissue-intrinsic regulates could serve potential therapeutic target for amelioration