The branched-chain amino acid transporter CD98 heavy chain facilitates the development of colonic macrophages associated with apoptosis in macrophage progenitors

CX3CR1+ mononuclear phagocytes extend processes into the intestinal lumen to monitor the intestinal microbiota as well as the chymus. Whether the constituents of the chymus are required for macrophages is not known. Moreover, the molecular mechanisms that control the intestinal ability to distinguish between "innocuous" and "dangerous" antigens remain poorly understood although macrophages play a key role in this process. A comprehensive macrophage development is critical for gut macrophages performing crucial tasks in the intestinal immune system. However, the underlying mechanisms of this development remain elusive. The amino acid transporter CD98, which was first identified as a lymphocyte activation marker, is a multifunctional protein and is associated with a variety of activities, such as those of amino acid transporters, integrin regulators, and fusion regulators. CD98hc interacts with certain integrin β-subunits to mediate signaling events and consequently controls cell migration, survival, and proliferation. To assess the role of branched-chain amino acids on the development of gut macrophages, we generated an inducible knock-out mouse model for the branched-chain amino acid transporter CD98hc specifically in CX3CR1+ intestinal macrophages. We showed that CD98 deficient macrophages attenuate the severity of dextran sodium sulfate-induced colitis clinically, endoscopically, and histologically. Single-cell RNA sequencing of colonic lamina propria macrophages obtained from unmanipulated and healthy mice revealed that silencing CD98 blocks the ‘monocyte waterfall’-development to mature macrophages. Further, we observed that the arrest in macrophage development is associated with increased expression of apoptotic genes. Moreover, patients with Crohn’s disease and ulcerative colitis are characterized by high CD98 expression. Our results demonstrate that CD98 plays a pivotal role in intestinal homeostasis by influencing the development of gut macrophages.