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IL-4i1 regulates immune protection during Mycobacterium tuberculosis infection. BACKGROUND: Interleukin-4-induced gene 1 (IL-4i1) encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells, inhibits T-cell proliferation, regulates B-cell activation, drives macrophage polarization and modulates Th1 inflammatory immune responses, but its role in bacterial infections is understudied. METHODS: Herein, we evaluated IL-4i1 deletion in macrophages and mice upon infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and pro-inflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment and macrophage activation were assessed at the early and chronic stages of Mtb infection. RESULTS: IL-4i1 -/- mice displayed increased protection against acute H37Rv and HN878 and chronic HN878 Mtb infections; with reduced lung bacterial burdens and altered antigen-presenting cell (APC) responses when compared to wild-type mice. Moreover, "M1-like" interstitial macrophage numbers, nitrite and interferon production were significantly increased in IL-4i1 -/- mice when compared to wild-type mice during acute Mtb HN878 infection. CONCLUSIONS: Together, these data suggest that IL-4i1 regulates APC-mediated inflammatory responses during acute and chronic Mtb infection. Hence IL-4i1 targeting has the potential as an immunomodulatory target for host-directed therapy.