If the conditional deletion of CD98hc affects the development of CX3CR1 + intestinal monocytes and macrophages, presumably, this will impact the colitis severity. On the other hand, the oral treatment of mice with nanoparticles loaded with CD98hc small interfering RNA attenuated the severity of colitis 22. In the context of inflammatory bowel disease, the overexpression of CD98hc in intestinal epithelial cells leads to exacerbated colitis and colitis-associated cancer 21. Furthermore, CD98hc also binds to β1A and β3 integrins 19, which mediates adhesive signals to the local microenvironment in the bone marrow niche and thereby facilitates the progression of acute myelogenous leukemia 20. It is now clear that the role of CD98hc extends beyond being only an activation marker for example, it is required for clonal expansion of T cells and B cells 17, 18. The glycoprotein CD98hc, which was termed initially 4F2 and identified as an activation antigen of lymphocytes 15, is an integral membrane protein that contains a single-pass heavy chain (encoded by the genes SLC3A2 for human and Slc3a2 for mouse), which is covalently linked to a multi-pass light chain (LAT1 and LAT2, encoded by the genes SLC7A5/Slc7a5 and SLC7A8/Slc7a8, respectively) via a disulfide bond 16. Because both monocytes and macrophages express CX3CR1 10, we bred CD98hc flox/flox with Cx3cr1 CreER-YFP mice to conditionally delete CD98hc (cKO) in these populations. We thought that the deletion of CD98hc in CX3CR1 + intestinal macrophages might allow studying the requirement of branched-chain amino acids for their development and maturation. It has recently been shown, that the branched-chain amino acid transporter CD98, composed of a heavy (CD98hc) and light (CD98lc) subunit, is highly expressed by monocytes and macrophages, and plays an essential role in the activation and functions of macrophages 14. For example, the influx of leucine in human macrophages or the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) in mice promotes the production of pro-inflammatory cytokines 12, 13. Several lines of evidence have implicated that sensing of nutrients by macrophages assists their development 11. However, the sequence of molecular events leading to the stepwise differentiation of monocytes into lamina propria macrophages is yet to be understood. Accordingly, monocytes stepwise downregulate the expression of Ly6C high and acquire F4/80, CD64, CD11c, and CX3CR1 10. Tracking of monocytes after adoptive transfer later suggested that monocytes mature to lamina propria F4/80 + CX3CR1 high MHCII + macrophages through different stages of monocyte intermediates following a “monocyte waterfall”-development 10. This phenomenon is an exception to most other tissues, where macrophages are embryonically derived, self-renewed, and not replaced continuously by monocytes 7, 8, 9.Īdoptively transferred monocytes from Cx3cr1-GFP mice, tracked in recipient animals depleted in CD11c + cells, give rise to lamina propria CX3CR1 + macrophages 3, 4. These monocytes originate from blood, enter the gut, and mature into short-lived colonic macrophages locally 3, 4, or to long-lived Tim-4 and surface CD4 expressing lamina propria macrophages 5 and to long-lived submucosa and myenteric plexus macrophages, which also could be remnants of embryonic-derived macrophages 6. In order to maintain the integrity of the colonic barrier, which is in constant contact with the environment, monocytes continually replenish the tissue-resident macrophage pool 2. Macrophages are one of the most abundant cell populations in the colonic lamina propria, where they remove apoptotic cell bodies, survey the intestinal content, and ingest and kill microbes that have passed the epithelial barrier 1. Our results show that CD98hc deletion changes the development of colonic macrophages. The change in the macrophage development after deletion of CD98hc is associated with increased apoptotic gene expression. Single-cell RNA sequencing of colonic lamina propria macrophages revealed that conditional deletion of CD98hc alters the “monocyte waterfall”-development to MHC II + macrophages. The relatively selective deletion of CD98hc in macrophage populations leads to attenuated severity of chemically-induced colitis that we assessed by clinical, endoscopic, and histological scoring. To investigate the function of branched-chain amino acids in the development of gut macrophages, an inducible knock-out mouse model for the branched-chain amino acid transporter CD98hc in CX3CR1 + macrophages was generated. However, the underlying mechanisms of macrophage development in the colon remain elusive. Comprehensive development is critical for gut macrophages being essential for the intestinal immune system.
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