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In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin\u2010a and HlSerpin\u2010b, from the hard tick <jats:italic>Haemaphysalis longicornis<\/jats:italic> of China. Recombinant HlSerpin\u2010a and HlSerpin\u2010b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin\u2010a and HlSerpin\u2010b suppressed the expression of inflammatory cytokines such as TNF\u2010\u03b1, interleukin (IL)\u20106 and IL\u20101\u03b2 from lipopolysaccharide\u2010stimulated mouse bone\u2010marrow\u2010derived macrophages (BMDMs) or mouse bone\u2010marrow\u2010derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin\u2010a, named SA\u2010RCL, showed similar biological activities as HlSerpin\u2010a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full\u2010length HlSerpin\u2010a and SA\u2010RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA\u2010RCL are dependent on their protease inhibitory activity. Finally, we showed that both full\u2010length HlSerpins and SA\u2010RCL can relieve the joint swelling and inflammatory response in collagen\u2010induced mouse arthritis models. These results suggested that HlSerpin\u2010a and HlSerpin\u2010b are two functional arthropod serpins, and the minimal reactive peptide SA\u2010RCL is a potential candidate for drug development against inflammatory diseases.<\/jats:p>","DOI":"10.1111\/imm.13130","type":"journal-article","created":{"date-parts":[[2019,10,13]],"date-time":"2019-10-13T11:39:38Z","timestamp":1570966778000},"page":"109-120","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The immunosuppressive functions of two novel tick serpins, HlSerpin\u2010a and HlSerpin\u2010b, from <i>Haemaphysalis longicornis<\/i>"],"prefix":"10.1111","volume":"159","author":[{"given":"Fanqi","family":"Wang","sequence":"first","affiliation":[{"name":"Institutes of Biology and Medical Sciences Jiangsu Key Laboratory of Infection and Immunity Soochow University Suzhou 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