Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Front Immunol. 2020 May 12;11:886. doi: 10.3389/fimmu.2020.00886. eCollection 2020.
Macrophages host infection, which causes cutaneous Leishmaniasis in humans. In the murine model, resistance to infection depends on the host immunity mediated by CD4 T-cell cytokines and macrophages. In association to other stimuli, the Th1 cytokine IFN-γ induces NO-mediated microbial killing by M1/classically-activated macrophages. By contrast, the Th2 cytokine IL-4 promotes M2/alternatively activated macrophages, which express arginase-1 and shelter infection. Other cytokines, such as RANKL, might also participate in the crosstalk between T cells and macrophages to restrict parasite infection. RANKL and its receptor RANK are known to play an essential role in bone remodeling, by inducing osteoclatogenesis. It has also been shown that RANKL stimulates antigen-presenting cells, such as DCs and macrophages, to enhance T cell responses. Here we investigated how RANKL directly modulates the effector macrophage phenotypes and immunity to parasites. We found that inflammatory peritoneal macrophages from B6 mice express RANK and M2 features, such as CD301 (MGL) and CD206 (mannose receptor). Nonetheless, treatment with RANKL or IFN-γ induced macrophage differentiation into more mature F40/80 macrophages able to produce IL-12 and TNF-α. In parallel, macrophages treated with RANKL, IFN-γ, or RANKL along with IFN-γ progressively downregulated the expression of the M2 hallmarks MGL, arginase-1, and CCL17. Moreover, a synergism between IFN-γ and RANKL enhanced inducible NO synthase (iNOS) expression and NO production by macrophages. These results are consistent with the idea that RANKL helps IFN-γ to induce a M2-like to M1 phenotype shift. Accordingly, concomitant treatment with RANKL and IFN-γ promoted macrophage-mediated immunity to , by inducing NO and ROS-dependent parasite killing. Furthermore, by cooperating with IFN-γ, endogenous RANKL engages CD4 T-cell help toward -infected macrophages to upregulate M1 and Th1 cytokine responses. Therefore, RANKL, in combination with IFN-γ, is a potential local therapeutic tool to improve immune responses in Leishmaniasis, by skewing M2-like into effector M1 macrophages.
巨噬细胞是感染的宿主，会导致人类发生皮肤利什曼病。在鼠模型中，对感染的抵抗力取决于由 CD4 T 细胞细胞因子和巨噬细胞介导的宿主免疫。与其他刺激物一起，Th1 细胞因子 IFN-γ 通过 M1/经典激活的巨噬细胞诱导 NO 介导的微生物杀伤。相比之下，Th2 细胞因子 IL-4 促进表达精氨酸酶-1 并庇护感染的 M2/替代激活的巨噬细胞。其他细胞因子，如 RANKL，也可能参与 T 细胞和巨噬细胞之间的串扰，以限制寄生虫感染。已知 RANKL 和其受体 RANK 通过诱导破骨细胞生成在骨重塑中发挥重要作用。还表明 RANKL 刺激抗原呈递细胞（如 DC 和巨噬细胞）以增强 T 细胞反应。在这里，我们研究了 RANKL 如何直接调节效应巨噬细胞表型和对寄生虫的免疫。我们发现 B6 小鼠的炎症性腹膜巨噬细胞表达 RANK 和 M2 特征，如 CD301（MGL）和 CD206（甘露糖受体）。尽管如此，用 RANKL 或 IFN-γ 处理会诱导巨噬细胞分化为更成熟的 F40/80 巨噬细胞，能够产生 IL-12 和 TNF-α。同时，用 RANKL、IFN-γ 或 RANKL 与 IFN-γ 处理的巨噬细胞逐渐下调 M2 标志物 MGL、精氨酸酶-1 和 CCL17 的表达。此外，IFN-γ 和 RANKL 之间的协同作用增强了巨噬细胞诱导型一氧化氮合酶（iNOS）的表达和 NO 的产生。这些结果与 RANKL 有助于 IFN-γ 诱导 M2 样向 M1 表型转变的观点一致。因此，同时用 RANKL 和 IFN-γ 处理可通过诱导 NO 和 ROS 依赖性寄生虫杀伤来促进巨噬细胞介导的对的免疫。此外，通过与 IFN-γ 合作，内源性 RANKL 使 CD4 T 细胞辅助感染的巨噬细胞上调 M1 和 Th1 细胞因子反应。因此，RANKL 与 IFN-γ 联合使用是一种潜在的局部治疗工具，可通过将 M2 样转变为效应 M1 巨噬细胞来改善利什曼病中的免疫反应。
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