Atg16l1 promotes lung transplant tolerance by regulating glycolysis in macrophages

Abstract

Lung transplant survival is limited by the development of chronic lung allograft dysfunction (CLAD), a type of graft rejection that lacks effective treatments. Autophagy plays a crucial role in maintaining cellular homeostasis. In a single-nucleotide polymorphism screen, we found that lung recipients with two copies of a common hypofunctional genetic variant of autophagy-related 16-like 1 rs2241880 (ATG16L1T300A/T300A), known to deplete this protein from macrophages, were more likely to develop early CLAD. To understand this, we used a mouse orthotopic lung transplant model. Recipients encoding myeloid cell-specific deletion of Atg16l1 (Atg16l1{Delta}/{Delta}) or who harbor an engineered orthologous mutation (Atg16l1T316A/T316A) showed similar susceptibility to CLAD. Transcript profiling and mitochondrial tracking studies indicated that increased mitochondrial damage and decreased autophagic removal of mitochondria in Atg16l1-deficient macrophages were associated with heightened activation of the hypoxia-inducible factor 1 (Hif1) pathway and accumulation of glycolytic transcripts. Metabolic analysis revealed reduced oxidative phosphorylation, increased glycolytic activity, and higher IL-1{beta} expression in Atg16l1-deficient macrophages. Notably, the development of CLAD in Atg16l1{Delta}/{Delta} lung recipients could be significantly prevented by additionally deleting Hif1 in myeloid cells or by treating with the glycolysis inhibitor 2-deoxyglucose. Our results show how a common autophagy-related genetic variant disrupts macrophage metabolism and impairs lung transplant tolerance, pointing toward potential therapeutic strategies to combat CLAD.