Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
Department of Life Sciences, National Central University, Zhongli District, Taoyuan, Taiwan.
Mediators Inflamm. 2018 Dec 16;2018:3523642. doi: 10.1155/2018/3523642. eCollection 2018.
Psoriasis is a chronic inflammatory skin disorder that affects ~2%-3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7-9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7-9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7-9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7-9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7-9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
银屑病是一种慢性炎症性皮肤病，影响全球约 2%-3%的人口。在银屑病部位，内体 Toll 样受体 7、8 和 9（TLR7-9）的不适当和过度激活已被证明在银屑病的发病中起致病作用。巨噬细胞是一种主要的炎症细胞类型，可以分化为 M1 和 M2 表型。M1 巨噬细胞产生促炎细胞因子，M2 巨噬细胞产生抗炎细胞因子。这两种类型的巨噬细胞之间的平衡决定了各种炎症性疾病的进展；然而，内体 TLR 激活的银屑病炎症中巨噬细胞极化是否发挥作用尚未得到研究。在这项研究中，我们研究了与 TLR7-9 在银屑病进展中的致病作用相关的巨噬细胞的功能和机制。对数据库中临床数据的分析表明，银屑病组织中巨噬细胞标志物和炎症细胞因子的表达明显高于正常组织。在动物研究中，用咪喹莫特（TLR7 激动剂）处理时，敲除小鼠巨噬细胞可改善银屑病样反应。咪喹莫特诱导银屑病病变中 M1 巨噬细胞特征基因和细胞因子的表达。此外，用这种 TLR7 激动剂治疗可使银屑病病变中的巨噬细胞向更高的 M1/M2 比值转变。外源性和内源性 TLR7-9 配体均可激活 M1 巨噬细胞极化。M1 巨噬细胞表达的促炎细胞因子和 TLR7-9 水平高于 M2 巨噬细胞。这些结果表明，通过使巨噬细胞进入更具炎症状态并能够对其在银屑病部位的配体作出反应，TLR7-9 激活促使它们参与内体 TLR 激活的银屑病炎症，导致炎症反应放大。我们的结果还表明，阻断 M1 巨噬细胞极化可能是一种抑制这些 TLR 激活的银屑病炎症的策略。
