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Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment¹

Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan St. Beijing 100050, People’s Republic of China

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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the National Major Basic Research Program of China (2006CB503808) and from National Nature Scientific Foundation (30672468). Z.H. is also supported by Cheung-Kong Scholars Programme of Ministry of Education and by a Senior Oversea Chinese Scholar Fund from Ministry of Personnel of People’s Republic of China.

² H.-Z.Y. and B.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Zhuo-Wei Hu, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan St. Beijing, People’s Republic of China. E-mail address: huzhuowei{at}imm.ac.cn

⁴ Abbreviations used in this paper: PAMP, pathogen-associated molecular patterns; BALF, bronchoalveolar lavage fluid; BLM, bleomycin; DAMP, damage-AMP; DCs, dendritic cells; IOD, integrated OD; mDC, marrow-derived DC; pDC, plasmocytoid DC; Treg, regulatory T cell; WT, wide type; MMP, matrix metallopeptidase.