Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment
Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment
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DOI：
10.4049/jimmunol.182.1.692
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发表时间：
2009-01-01
影响因子：
4.4
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Yang, Hong-Zhen;Cui, Bing;Hu, Zhuo-Wei
肺纤维化是慢性肺损伤的结果，并且与高死亡率相关。尽管肺纤维化的发病机制仍然是一个谜，但免疫反应在肺损伤后伤口愈合过程的失调中起着关键作用，这导致了纤维化。越来越多的证据支持目前使用免疫抑制剂如皮质类固醇治疗肺纤维化的理论。在这项研究中，我们报告，博莱霉素（BLM），一个众所周知的纤维化剂作为TLR 2激动剂，诱导树突状细胞的成熟和细胞因子的释放。TLR 2的BLM活化介导肺中免疫应答的时间依赖性改变。这些反应导致在组织浸润促炎细胞和细胞因子的增加，在早期最初的BLM暴露后，在组织浸润抑制性免疫细胞和因子的增加，在后期BLM暴露后。然而，TLR 2缺乏减少了肺部炎症、损伤，随后减弱了肺纤维化。通过TLR 2中和抗体靶向TLR 2不仅显著降低动物死亡，而且保护动物免于肺纤维化的发展，并且通过调节BLM诱导的免疫抑制微环境来逆转已建立的肺纤维化。我们的研究表明，TLR 2是一个有前途的目标，为发展治疗药物对肺纤维化和消除免疫抑制细胞和因子通过免疫刺激剂是一种新的战略纤维增生性疾病。此外，将BLM与抗TLR 2 Ab或TLR 2拮抗剂组合用于癌症治疗将通过增强抗癌功效和减少全身性炎症和肺纤维化来改善BLM治疗概况。免疫学杂志，2009，182：692-702.
Pulmonary fibrosis is a consequence of chronic lung injury and is associated with a high mortality. Despite the pathogenesis of pulmonary fibrosis remaining as an enigma, immune responses play a critical role in the deregulation of wound healing process after lung injury, which leads to fibrosis. Accumulating evidence argues the rationales for current treatments of pulmonary fibrosis using immunosuppressive agents such as corticosteroids. In this study, we report that bleomycin (BLM), a well-known fibrogenic agent functioning as a TLR2 agonist, induced the maturation of dendritic cells and release of cytokines. The BLM activation of TLR2 mediated a time-dependent alteration of immune responses in the lung. These responses resulted in an increase in the tissue-infiltrating proinflammatory cells and cytokines in the early period initially following BLM exposure and an increase in the tissue-infiltrating suppressive immune cells and factors during the later period following BLM exposure. TLR2 deficiency, however, reduced pulmonary inflammation, injury, and subsequently attenuated pulmonary fibrosis. Targeting TLR2 by a TLR2-neutralizing Ab not only markedly decreased animal death but also protected animals from the development of pulmonary fibrosis and reversed the established pulmonary fibrosis through regulating BLM-induced immunosuppressive microenvironments. Our studies suggest that TLR2 is a promising target for the development of therapeutic agents against pulmonary fibrosis and that eliminating immunosuppressive cells and factors via immunostimulants is a novel strategy for fibro-proliferative diseases. Moreover, combining BLM with an anti-TLR2 Ab or TLR2 antagonist for cancer therapy will improve the BLM therapeutic profile by enhancing anti-cancer efficacy and reducing systemic inflammation and pulmonary fibrosis. The Journal of Immunology, 2009, 182: 692-702.