Dietary L-arginine supplementation cures chronic L. mexicana infection

Control of Leishmania (L.) requires IFNγ-dependent type 2 nitric oxide (NO) synthase (NOS2), an enzyme that converts L-arginine into citrulline and NO. NOS2 activity is counteracted by arginase (ARG) 1 and 2, which are induced by Th2 cytokines and cleave L-arginine into urea and ornithine, a precursor of polyamines necessary for cell proliferation. Recently, we observed that the expression of ARG1 steadily increased in L. mexicana-infected BALB/c and C57BL/6 mice during disease manifestation. Here, we studied the functional role of host cell arginases during L. mexicana induced chronic cutaneous leishmaniasis (CL).

L.mexicana infected C57BL/6 WT mice developed non-healing chronic CL, whereas mice with deletion of ARG1 in monocytes and macrophages (Arg1 ΔCx3cr1) exhibited a strongly reduced pathology and ultimately resolved their skin lesions despite parasite persistence. Mice lacking IL-10 in CD4+ T cells (Il10ΔCd4) revealed IL-10 as a factor inducing ARG1 during infection. Flow cytometry and scRNAseq analyses of skin lesions showed an enrichment of dermal myeloid subpopulations in WT mice, including a dominant cluster of ARG1+NOS2+ inflammatory macrophages that developed from recruited monocytes in an ARG1- and IFNγ-dependent manner. These macrophages expressed high levels of CXCL9/10, thereby entertaining a self-perpetuating cycle of inflammation, and served as a replicative niche for the parasites, because ARG1 restricted NOS2-mediated killing due to substrate competition. Additionally, the accumulation of ARG1+NOS2+ macrophages led to a long-lasting depletion of L-arginine in the skin as measured by metabolomics, which was not observed in ARG1-deficient healer mice. Based on this finding we treated infected mice with dietary L-arginine via the drinking water. Oral supplementation with L-arginine was able to prevent chronic CL in a prophylactic setting. Most strikingly, infected sick WT mice could be cured by the L-arginine treatment in a therapeutic setting.

Thus, metabolic reprogramming by L-arginine can resolve chronic skin inflammation in L. mexicana infection, which is induced and maintained by an ARG1-dependent pathogenic differentiation of monocytes.