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.