{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:12:29Z","timestamp":1780477949825,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,18]],"date-time":"2022-12-18T00:00:00Z","timestamp":1671321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Ministry of Education, Culture, Sports, Science, and Technology","award":["19K07949"],"award-info":[{"award-number":["19K07949"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4\/MIP-1\u03b2\u2014a specific ligand for CCR5 receptors\u2014was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression\u2014a marker of activated eosinophils\u2014as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)\u03b2, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFR\u03b2, and\/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.<\/jats:p>","DOI":"10.3390\/ijms232416149","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:25:46Z","timestamp":1671427546000},"page":"16149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation"],"prefix":"10.3390","volume":"23","author":[{"given":"Hanh Hong","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3755-3074","authenticated-orcid":false,"given":"Yoshiki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan Van","family":"Bui","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Department of Allergy and Clinical Immunology, Hanoi Medical University, Hanoi 116177, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6879-6303","authenticated-orcid":false,"given":"Yasutaka","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh Manh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-5505","authenticated-orcid":false,"given":"Akitoshi","family":"Mitani","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1659-1549","authenticated-orcid":false,"given":"Kensuke","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikiya","family":"Asako","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6324-721X","authenticated-orcid":false,"given":"Akira","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"},{"name":"Allergy Center, Kansai Medical University Hospital, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-8173","authenticated-orcid":false,"given":"Hiroshi","family":"Iwai","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2332\/allergolint.10-RAI-0231","article-title":"Eosinophilic chronic rhinosinusitis in Japan","volume":"59","author":"Ishitoya","year":"2010","journal-title":"Allergol. 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