Background Interleukin 4 (IL-4i1)–induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied. Methods We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory 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–deficient (IL-4i1−/−) mice displayed increased protection against acute H37Rv, HN878 and chronic HN878 Mt infections, with reduced lung bacterial burdens and altered APC responses compared with wild-type mice. Moreover, “M1-like” interstitial macrophage numbers, and nitrite and Interferon-γ production were significantly increased in IL-4i1−/− mice compared with 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 potential as an immunomodulatory target for host-directed therapy.

中文翻译：

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IL-4i1 对结核分枝杆菌感染期间免疫保护的调节

背景 白细胞介素 4 (IL-4i1) 诱导的基因 1 编码 L-苯丙氨酸氧化酶，可将苯丙氨酸分解代谢为苯丙酮酸。IL-4i1 主要由抗原呈递细胞 (APC) 表达，抑制 T 细胞增殖，调节 B 细胞活化，调节 T 细胞反应，并驱动巨噬细胞极化，但其在细菌感染中的作用尚未得到充分研究。方法 我们评估了巨噬细胞和小鼠在感染 H37Rv 和 W-Beijing 系高毒力 HN878 结核分枝杆菌 (Mtb) 菌株后的 IL-4i1 缺失。在体外和体内测量细菌生长和促炎反应。在 Mtb 感染的早期和慢性阶段评估了组织病理学分析、肺免疫细胞募集和巨噬细胞活化。结果 与野生型小鼠相比，IL-4i1 缺陷型 (IL-4i1-/-) 小鼠对急性 H37Rv、HN878 和慢性 HN878 Mt 感染的保护作用增强，肺细菌负荷降低，APC 反应改变。此外，在急性 Mtb HN878 感染期间，与野生型小鼠相比，IL-4i1-/- 小鼠的“M1 样”间质巨噬细胞数量以及亚硝酸盐和干扰素-γ 的产生显着增加。结论 总之，这些数据表明 IL-4i1 在急性和慢性 Mtb 感染期间调节 APC 介导的炎症反应。因此，IL-4i1 靶向具有作为宿主导向治疗的免疫调节靶点的潜力。在急性 Mtb HN878 感染期间，与野生型小鼠相比，IL-4i1-/- 小鼠的“M1 样”间质巨噬细胞数量以及亚硝酸盐和干扰素-γ 的产生显着增加。结论 总之，这些数据表明 IL-4i1 在急性和慢性 Mtb 感染期间调节 APC 介导的炎症反应。因此，IL-4i1 靶向具有作为宿主导向治疗的免疫调节靶点的潜力。在急性 Mtb HN878 感染期间，与野生型小鼠相比，IL-4i1-/- 小鼠的“M1 样”间质巨噬细胞数量以及亚硝酸盐和干扰素-γ 的产生显着增加。结论 总之，这些数据表明 IL-4i1 在急性和慢性 Mtb 感染期间调节 APC 介导的炎症反应。因此，IL-4i1 靶向具有作为宿主导向治疗的免疫调节靶点的潜力。