Interleukin-17A Promotes Initiation And Development Of Fibrosis Through Inhibiting Activation Of Autophagy

Tissue remolding diseases has become one of the most serious public health problem worldwide. More than45%of the global annual deaths are due to the kinds of tissue remodeling diseases. Fibrosis is not only the typical common pathological changes in the tissue remodeling diseases, but also the core pathological changes of a variety of chronic diseases, and the pivotal reason of the persistent and repetition of the chronic diseases. The mechanism of initiation and development of fibrosis is still dimness. The previous studies have shown that multiple signaling pathways, such as Smads and β-catenin signaling pathway, were involved in mediating the expression of profibrotic molecules. Myofibroblast, a lineage of the activation of fibroblast is recommended as the cell biological basis of the initiation and development of fibrosis. After the injury occurs, the stimuli, such as of TGF-β1, IL-6et al., induce trans-differentiation of a variety of cells to the myofibroblasts which promote the development of fibrosis by synthesizing and releasing large amounts of collagen and extracellular matrix.The nature of the local chronic inflammation determined by the nature of the immune microenvironment around the lesions determines the prognosis of the fibrosis-related diseases. Previous studies have shown that the Th2-dominated suppressing immune microenvironment exacerbated the development of tissue fibrosis, but Th1-type immune microenvironment attenuated fibrotic pathological changes.Th17cells is a recently identified T helper cell subtype independent of Th1/2. Th17mediates the tissue immune responses by its the main effecter cytokine IL-17A, which plays an important role in a variety of inflammation-related diseases and autoimmune diseases. We wondered whether the Th17immune response and the IL-17A is involved in the initiation and development of fibrosis.We firstly explore the relationship between IL-17A and fibrosis in both animal and cellular level. The results showed that IL-17A could induce the expression of fibrogenic factor TGF-β1secretion, promote the EMT and activation of myofibroblast to synthesis and secret the collagen in vitro. The expression of IL-17A was also significantly increased in bleomycin-induced pulmonary fibrosis, bile duct ligation induced liver fibrosis and abdominal aortic coarctation induced myocardial fibrosis in mice. These results suggested that IL-17A was involved in the initiation and development of tissue fibrosis. Then, we used anti-IL-17A neutralizing antibody to treat the mice with fibrotic diseases. The results showed that blocking IL-17A could significantly attenuate the bleomycin-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, bile duct ligation induced liver fibrosis and abdominal aorta contraction induced myocardial fibrosis in mice and the level of local inflammation of fibrosis, and shift the nature of inflammatory environment around the fibrotic tissues. We recently found that autophagy, an effecter mechanisms of TLR4activation, was involved in the resolution of the chronic inflammation and the pulmonary and myocardial fibrosis after tissue injury. We found that blocking IL-17A can also restore the inhibited autophagic activity in bleomycin-induced pulmonary fibrosis, bile duct ligation induced liver fibrosis and abdominal aortic coarctation-induced myocardial fibrosis. We further found that of IL-17A could inhibit the autophagy activity directly, and suppress the autophagic components-related collagen degradation pathways. Moreover, pharmacological blocking autophagy activity could reverse the therapeutic effect of anti-IL-17A antibody on bleomycin-induced pulmonary fibrosis in mice.Our results suggested that IL-17A may participate in the development of a variety of tissue fibrosis through inducing the expression of TGF-β1, and promoting activation of myofibroblasts or directly inhibiting the autophagy activity. The study of IL-17A, a potential therapeutic target of tissue fibrotic diseases, was very important to the clinical application and drug development.