Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, California.
Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, California; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Am J Pathol. 2013 Oct;183(4):1209-1222. doi: 10.1016/j.ajpath.2013.06.017. Epub 2013 Aug 3.
Galectin-3 is a β-galactoside-binding animal lectin with diverse functions, including regulation of T helper (Th) 1 and Th2 responses. Current data indicate that galectin-3 expressed in dendritic cells (DCs) may be contributory. Th17 cells have emerged as critical inducers of tissue inflammation in autoimmune disease and important mediators of host defense against fungal pathogens, although little is known about galectin-3 involvement in Th17 development. We investigated the role of galectin-3 in the induction of Th17 immunity in galectin-3-deficient (gal3(-/-)) and gal3(+/+) mouse bone marrow-derived DCs. We demonstrate that intracellular galectin-3 negatively regulates Th17 polarization in response to the dectin-1 agonist curdlan (a β-glucan present on the cell wall of fungal species) and lipopolysaccharide, agents that prime DCs for Th17 differentiation. On activation of dectin-1, gal3(-/-) DCs secreted higher levels of the Th17-axis cytokine IL-23 compared with gal3(+/+) DCs and contained higher levels of activated c-Rel, an NF-κB subunit that promotes IL-23 expression. Levels of active Raf-1, a kinase that participates in downstream inhibition of c-Rel binding to the IL23A promoter, were impaired in gal3(-/-) DCs. Modulation of Th17 by galectin-3 in DCs also occurred in vivo because adoptive transfer of gal3(-/-) DCs exposed to Candida albicans conferred higher Th17 responses and protection against fungal infection. We conclude that galectin-3 suppresses Th17 responses by regulating DC cytokine production.
半乳糖凝集素-3 是一种具有多种功能的 β-半乳糖苷结合动物凝集素，包括调节辅助性 T 细胞（Th）1 和 Th2 反应。目前的数据表明，树突状细胞（DCs）中表达的半乳糖凝集素-3 可能是促成因素。Th17 细胞已成为自身免疫性疾病中组织炎症的关键诱导剂，也是宿主防御真菌病原体的重要介质，尽管关于半乳糖凝集素-3 参与 Th17 细胞发育的了解甚少。我们研究了半乳糖凝集素-3 在半乳糖凝集素-3 缺陷（gal3(-/-)）和 gal3(+/+)小鼠骨髓来源的 DC 中诱导 Th17 免疫中的作用。我们证明，细胞内半乳糖凝集素-3 负调节对 dectin-1 激动剂凝乳多糖（真菌细胞壁上存在的一种β-葡聚糖）和脂多糖的 Th17 极化反应，这些因子可使 DC 向 Th17 分化。在 dectin-1 激活后，gal3(-/-) DC 分泌的 Th17 轴细胞因子 IL-23 水平高于 gal3(+/+) DC，并且含有更高水平的激活的 c-Rel，c-Rel 是一种 NF-κB 亚基，可促进 IL-23 的表达。gal3(-/-) DC 中参与下游抑制 c-Rel 与 IL23A 启动子结合的激酶活性 Raf-1 的水平受损。半乳糖凝集素-3 在 DC 中对半乳糖凝集素-3 的调节也发生在体内，因为暴露于白色念珠菌的 gal3(-/-) DC 的过继转移赋予了更高的 Th17 反应和对真菌感染的保护。我们的结论是，半乳糖凝集素-3 通过调节 DC 细胞因子的产生来抑制 Th17 反应。
