School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Clin Exp Immunol. 2012 May;168(2):165-77. doi: 10.1111/j.1365-2249.2012.04567.x.
Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b(+) macrophages and CD4(+) T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage.
临床上可用的抗肿瘤坏死因子 (TNF) 生物制剂，可抑制 TNF 的可溶性 (sTNF) 和跨膜形式 (tmTNF)，从而消除所有 TNF 信号转导，已成功治疗包括葡萄膜炎在内的自身免疫性疾病。这些药物可能具有严重的副作用，如潜伏结核分枝杆菌的再激活，因此，更特异性地抑制 TNF 信号通路可能在保持临床疗效的同时减少不良反应。为了确定特异性抑制 sTNF 对巨噬细胞激活和迁移的影响，我们使用了葡萄膜炎的小鼠模型（实验性自身免疫性葡萄膜炎；EAU）。我们表明，选择性抑制 sTNF 足以通过限制炎症性 CD11b(+)巨噬细胞和 CD4(+)T 细胞向眼内迁移来抑制 EAU。然而，抑制 sTNF 和 tmTNF 两者都需要抑制干扰素-γ诱导的趋化因子受体 2、CD40、主要组织相容性复合体 II 和一氧化氮 (NO) 的上调，并且 tmTNF 信号转导足以介导组织损伤。实际上，单独抑制 sTNF 并未抑制疾病，并且迁移到眼睛中的炎症细胞被激活，产生 NO，从而对视网膜造成结构损伤。相反，抑制 sTNF 和 tmTNF 都抑制了巨噬细胞的激活，从而抑制了疾病。我们得出结论，sTNF 是炎症细胞浸润靶组织所必需的，但在组织部位，抑制 sTNF 和 tmTNF 两者都需要抑制巨噬细胞激活并防止组织损伤。
