{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:26:42Z","timestamp":1792099602420,"version":"4.4.0"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cystic Fibrosis Foundation, USA","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"Cystic Fibrosis Foundation, USA","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"Cystic Fibrosis Foundation, USA","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"Cystic Fibrosis Foundation, USA","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"Cystic Fibrosis Foundation, USA","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]},{"name":"Children Health Foundation","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"Children Health Foundation","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"Children Health Foundation","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"Children Health Foundation","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"Children Health Foundation","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]},{"name":"Australian Cystic Fibrosis Innovation grant from the Australian Cystic Fibrosis Research Trust","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"Australian Cystic Fibrosis Innovation grant from the Australian Cystic Fibrosis Research Trust","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"Australian Cystic Fibrosis Innovation grant from the Australian Cystic Fibrosis Research Trust","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"Australian Cystic Fibrosis Innovation grant from the Australian Cystic Fibrosis Research Trust","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"Australian Cystic Fibrosis Innovation grant from the Australian Cystic Fibrosis Research Trust","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC) project","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC) project","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC) project","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC) project","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC) project","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]},{"name":"Australian Research Council Discovery Early Career Award","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"Australian Research Council Discovery Early Career Award","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"Australian Research Council Discovery Early Career Award","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"Australian Research Council Discovery Early Career Award","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"Australian Research Council Discovery Early Career Award","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]},{"name":"National Health and Medical Research Council (NHMRC), Australia","award":["SLY16AO"],"award-info":[{"award-number":["SLY16AO"]}]},{"name":"National Health and Medical Research Council (NHMRC), Australia","award":["21-027721"],"award-info":[{"award-number":["21-027721"]}]},{"name":"National Health and Medical Research Council (NHMRC), Australia","award":["21-025192"],"award-info":[{"award-number":["21-025192"]}]},{"name":"National Health and Medical Research Council (NHMRC), Australia","award":["APP1159106"],"award-info":[{"award-number":["APP1159106"]}]},{"name":"National Health and Medical Research Council (NHMRC), Australia","award":["DE180100524"],"award-info":[{"award-number":["DE180100524"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1\/M2 polarized macrophages in CF. Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1\/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1\/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected; however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM d\u2019d not restore endocytosis in CF, another essential feature of M2 macrophages. Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1\/2 activation for bacterial uptake.<\/jats:p>","DOI":"10.3390\/cells13020166","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T04:56:59Z","timestamp":1705381019000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3782-345X","authenticated-orcid":false,"given":"Abdullah A.","family":"Tarique","sequence":"first","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Tuladhar","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-7402","authenticated-orcid":false,"given":"Dean","family":"Kelk","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelufa","family":"Begum","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Lucas","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Stow","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E.","family":"Wainwright","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"},{"name":"Respiratory and Sleep Medicine, Queensland Children\u2019s Hospital, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-7139","authenticated-orcid":false,"given":"Scott C.","family":"Bell","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"},{"name":"Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD 4032, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Sly","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Fantino","sequence":"additional","affiliation":[{"name":"Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/S2213-2600(22)00165-5","article-title":"The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): A phase 3, randomised, double-blind, placebo-controlled clinical trial","volume":"10","author":"Stick","year":"2022","journal-title":"Lancet Respir. 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