Biosciences and Biotechnology Graduate Program, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil.
Laboratory of Immunoparasitology of Neglected Diseases and Cancer (LIDNC), Department of Pathological Sciences, State University of Londrina, Londrina, Brazil.
Front Cell Infect Microbiol. 2021 Oct 1;11:687633. doi: 10.3389/fcimb.2021.687633. eCollection 2021.
Cutaneous leishmaniasis is a zoonotic infectious disease broadly distributed worldwide, causing a range of diseases with clinical outcomes ranging from self-healing infections to chronic disfiguring disease. The effective immune response to this infection is yet to be more comprehensively understood and is fundamental for developing drugs and vaccines. Thus, we used experimental models of susceptibility (BALB/c) and partial resistance (C57BL/6) to infection to investigate the local profile of mediators involved in the development of cutaneous leishmaniasis. We found worse disease outcome in BALB/c mice than in C57BL/6 mice, with almost 15 times higher parasitic load, ulcerated lesion formation, and higher levels of IL-6 in infected paws. In contrast, C57BL/6 presented higher levels of IFN-γ and superoxide anion after 11 weeks of infection and no lesion ulcerations. A peak of local macrophages appeared after 24 h of infection in both of the studied mice strains, followed by another increase after 240 h, detected only in C57BL/6 mice. Regarding M1 and M2 macrophage phenotype markers [iNOS, MHC-II, CD206, and arginase-1 (Arg-1)], we found a pronounced increase in Arg-1 levels in BALB/c after 11 weeks of infection, whereas C57BL/6 showed an initial predomination of markers from both profiles, followed by an M2 predominance, coinciding with the second peak of macrophage infiltration, 240 h after the infection. Greater deposition of type III collagen and lesion resolution was also observed in C57BL/6 mice. The adoptive transfer of macrophages from C57BL/6 to infected BALB/c at the 11th week showed a reduction in both edema and the number of parasites at the lesion site, in addition to lower levels of Arg-1. Thus, C57BL/6 mice have a more effective response against , based on a balance between inflammation and tissue repair, while BALB/c mice have an excessive Arg-1 production at late infection. The worst evolution seems to be influenced by recruitment of Arg-1 related macrophages, since the adoptive transfer of macrophages from C57BL/6 mice to BALB/c resulted in better outcomes, with lower levels of Arg-1.
皮肤利什曼病是一种广泛分布于全球的人畜共患传染病，可引起多种疾病，其临床结局从自限性感染到慢性毁容性疾病不等。对这种感染的有效免疫反应尚未得到更全面的理解，对于开发药物和疫苗至关重要。因此，我们使用易感性（BALB/c）和部分抗性（C57BL/6）的感染实验模型来研究参与皮肤利什曼病发生的局部介质谱。我们发现 BALB/c 小鼠的疾病结局比 C57BL/6 小鼠差，寄生虫载量高 15 倍，感染足形成溃疡性病变，IL-6 水平更高。相比之下，C57BL/6 在感染 11 周后表现出更高水平的 IFN-γ和超氧阴离子，且没有病变溃疡。在两种研究的小鼠品系中，感染后 24 小时出现局部巨噬细胞峰值，240 小时后再次增加，仅在 C57BL/6 小鼠中检测到。在感染后 24 小时，两种研究的小鼠品系中都出现了明显的 Arg-1 水平升高，而在 C57BL/6 中则观察到了 M1 和 M2 巨噬细胞表型标志物（iNOS、MHC-II、CD206 和精氨酸酶-1（Arg-1））的显著增加。在感染 11 周后，BALB/c 中的 Arg-1 水平明显升高，而 C57BL/6 则显示出两种表型标志物的初始优势，随后是 M2 优势，与感染后 240 小时的第二次巨噬细胞浸润高峰相一致。在 C57BL/6 小鼠中也观察到了更多的 III 型胶原沉积和病变消退。在第 11 周时，将巨噬细胞从 C57BL/6 转移到感染的 BALB/c 中，除了 Arg-1 水平降低外，还减少了病变部位的水肿和寄生虫数量。因此，C57BL/6 小鼠对有更强的反应，基于炎症和组织修复之间的平衡，而 BALB/c 小鼠在晚期感染时会产生过多的 Arg-1。最糟糕的病情发展似乎受到 Arg-1 相关巨噬细胞募集的影响，因为将 C57BL/6 小鼠的巨噬细胞转移到 BALB/c 中可改善结果，Arg-1 水平降低。
