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Studies have revealed that hyaluronic acid (HA) may exert different properties depending on their molecular size. High molecular weight HA (<jats:styled-content>&gt;<\/jats:styled-content>&gt;1,000\u2009kDa; HMW\u2010HA) displays immunosuppressive properties, whereas low molecular weight HA (&lt;800\u2009kDa; LMW\u2010HA) induces proinflammatory responses. The role of HMW\u2010HA interaction with CD44, a major HA receptor, in neuroinflammatory responses has not been fully elucidated. The purpose of this experimental study was to investigate the effects of topical applications of HMW\u2010HA on the sciatic nerve injury in an adult rat model. At the crush site on the sciatic nerve, the recordings of compound muscle action potential (CMAP) and the levels of several proteins related to inflammatory response were assessed at time intervals of 2, 4, and 6\u2009weeks postsurgery. Here, we show that the recovery effect of HMW\u2010HA treatment had significantly shortened latency and increased amplitude of CMAP compared with crushed alone, crushed plus \u03b3\u2010secretase inhibitor with or without HA treatment at 6\u2009weeks after surgery. Our data reveal that HMW\u2010HA could downregulate the expression of IL1\u2010\u03b2, TLR4, and MMP\u20109, whereas these proteins expression were increased when the CD44\u2010ICD activity was inhibited using \u03b3\u2010secretase inhibitor. Our findings demonstrated a novel role of CD44\u2010ICD in HA\u2010mediated recovery of peripheral nerve injury. Clinical relevance: an alternative for the regeneration of peripheral nerve injury.<\/jats:p>","DOI":"10.1002\/jbm.b.34731","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T08:44:27Z","timestamp":1614847467000},"page":"673-680","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["High molecular weight form of hyaluronic acid reduces neuroinflammatory response in injured sciatic nerve via the intracellular domain of <scp>CD44<\/scp>"],"prefix":"10.1002","volume":"109","author":[{"given":"I\u2010Ming","family":"Jou","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery E\u2010Da Hospital\/I\u2010Shou University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung\u2010Tai","family":"Wu","sequence":"additional","affiliation":[{"name":"GEG Orthopedic Clinic  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che\u2010Chia","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Chang","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhy\u2010Shrian","family":"Huang","sequence":"additional","affiliation":[{"name":"R&amp;D Division, Maxigen Biotech Inc.  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