{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:32:12Z","timestamp":1786631532668,"version":"build-2736575974"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prototypical type 2 airway disease in which tissue eosinophilia persists. That persistence is conventionally attributed to excess recruitment and to slowed apoptosis. Both explanations concern arrival and survival, and neither specifies what becomes of an eosinophil once it has died. That step is efferocytosis, the receptor-guided ingestion of apoptotic cells by macrophages, which differs from microbial phagocytosis in its ligands, its signaling output and its metabolic consequences. We establish this distinction first, because it decides which published datasets qualify as evidence and which do not. We then grade the surviving evidence and propose a cascade-anchored model in which failure is localized to three candidate lesions in the polyp macrophage: loss of an interleukin-10-dependent, MerTK-competent subset; a receptor repertoire skewed toward AXL and TIM-4 in which expression is uncoupled from productive ingestion; and an execution block at the phosphoinositide and Rac1 module. This model assigns the macrophage subsets reported in CRSwNP, including IL-10-deficient, ALOX15-positive, TIM-4-positive, TIPE2-positive, HMOX1-high and INPP4A-deficient populations, to defined steps rather than to a\n                    <jats:italic>polarization<\/jats:italic>\n                    label. We restate the shedding hypothesis as reduced surface receptor availability and reconcile a discordant tissue sheddase dataset. We explain why locally raised pro-resolving mediators cannot compensate when the receptor executing their action is absent, filter candidate therapies through the constraints of a colonized mucosal barrier, and note that the same receptors are targeted for inhibition in oncology. Finally, we specify the measurements that would refute the model.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1938524","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:44:48Z","timestamp":1786628688000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Efferocytosis failure in chronic rhinosinusitis with nasal polyps: receptor-level mechanisms of unresolved type 2 inflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Sihai","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4193\/Rhin20.600","article-title":"European position paper on rhinosinusitis and nasal polyps 2020","volume":"58","author":"Fokkens","year":"2020","journal-title":"Rhinology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.05.041","article-title":"Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania","volume":"138","author":"Wang","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.1016\/j.jaip.2019.05.009","article-title":"Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis","volume":"7","author":"Stevens","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2015.29.4231","article-title":"Predictive significance of tissue eosinophilia for nasal polyp recurrence in the Chinese population","volume":"29","author":"Lou","year":"2015","journal-title":"Am J Rhinol Allergy"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.02.016","article-title":"Mechanisms and pathogenesis of chronic rhinosinusitis","volume":"149","author":"Kato","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41580-020-0232-1","article-title":"The clearance of dead cells by efferocytosis","volume":"21","author":"Boada-Romero","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0240-6","article-title":"Efferocytosis in health and disease","volume":"20","author":"Doran","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01070-5","article-title":"After cell death: the molecular machinery of efferocytosis","volume":"55","author":"Moon","year":"2023","journal-title":"Exp Mol Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.034","article-title":"TAM receptors are pleiotropic inhibitors of the innate immune response","volume":"131","author":"Rothlin","year":"2007","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.cmet.2020.01.001","article-title":"Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury","volume":"31","author":"Yurdagul","year":"2020","journal-title":"Cell Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.637778","article-title":"Lysosome-dependent LXR and PPAR\u03b4 activation upon efferocytosis in human macrophages","volume":"12","author":"Mota","year":"2021","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1111\/j.1398-9995.2010.02498.x","article-title":"Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis","volume":"66","author":"Krysko","year":"2011","journal-title":"Allergy"},{"key":"B13","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.jaci.2017.10.038","article-title":"Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis","volume":"141","author":"Choi","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1016\/j.jaci.2018.01.029","article-title":"Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation","volume":"142","author":"Felton","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00302","article-title":"Eosinophils in the lung: modulating apoptosis and efferocytosis in airway inflammation","volume":"5","author":"Felton","year":"2014","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1016\/j.jaci.2017.03.024","article-title":"Diminished airway macrophage expression of the Axl receptor tyrosine kinase is associated with defective efferocytosis in asthma","volume":"140","author":"Grabiec","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/j.jaci.2012.09.028","article-title":"Obesity impairs apoptotic cell clearance in asthma","volume":"131","author":"Fernandez-Boyanapalli","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201311-2069OE","article-title":"Theirs but to die and do: primary lysis of eosinophils and free eosinophil granules in asthma","volume":"189","author":"Persson","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110449","article-title":"Overexpression of AXL on macrophages associates with disease severity and recurrence in chronic rhinosinusitis with nasal polyps","volume":"121","author":"Wang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-024-08450-1","article-title":"Aberrant expressions of TAM receptors are associated with postoperative recurrence in chronic rhinosinusitis with nasal polyps","volume":"281","author":"Zhou","year":"2024","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20230410","article-title":"Eosinophil extracellular traps in eosinophilic chronic rhinosinusitis induce Charcot-Leyden crystal formation and eosinophil recruitment","volume":"44","author":"Zhang","year":"2024","journal-title":"Biosci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1016\/j.jaci.2017.01.019","article-title":"Extracellular eosinophilic traps in association with Staphylococcus aureus at the site of epithelial barrier defects in patients with severe airway inflammation","volume":"139","author":"Gevaert","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800107","article-title":"Charcot-Leyden crystals activate the NLRP3 inflammasome and cause IL-1\u03b2 inflammation in human macrophages","volume":"202","author":"Rodriguez-Alcazar","year":"2019","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/path.4133","article-title":"Macrophage plasticity and polarization in tissue repair and remodelling","volume":"229","author":"Mantovani","year":"2013","journal-title":"J Pathol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112236","article-title":"Macrophages in CRSwNP: do they deserve more attention","volume":"134","author":"Fan","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200662","article-title":"Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction","volume":"189","author":"Zizzo","year":"2012","journal-title":"J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22218","article-title":"Deficiency in interleukin-10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps","volume":"8","author":"Wang","year":"2018","journal-title":"Int Forum Allergy Rhinol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.947983","article-title":"IL-10 family cytokines in chronic rhinosinusitis with nasal polyps: from experiments to the clinic","volume":"13","author":"Xuan","year":"2022","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/35075603","article-title":"Phagocytosis and clearance of apoptotic cells is mediated by MER","volume":"411","author":"Scott","year":"2001","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aar3721","article-title":"MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity","volume":"11","author":"Cai","year":"2018","journal-title":"Sci Signal"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2986","article-title":"Diversification of TAM receptor tyrosine kinase function","volume":"15","author":"Zag\u00f3rska","year":"2014","journal-title":"Nat Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.941608","article-title":"TIM-4 in macrophages contributes to nasal polyp formation through the TGF-\u03b21-mediated epithelial to mesenchymal transition in nasal epithelial cells","volume":"13","author":"Qin","year":"2022","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.jaci.2024.04.019","article-title":"ALOX15+ M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps","volume":"154","author":"Liu","year":"2024","journal-title":"J Allergy Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00652-4","article-title":"Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation","volume":"28","author":"Snodgrass","year":"2021","journal-title":"Cell Death Differ"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3866","article-title":"Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2","volume":"18","author":"Fayngerts","year":"2017","journal-title":"Nat Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21984","article-title":"Increased expression of TIPE2 in alternatively activated macrophages is associated with eosinophilic inflammation and disease severity in chronic rhinosinusitis with nasal polyps","volume":"7","author":"Yao","year":"2017","journal-title":"Int Forum Allergy Rhinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-024-01855-y","article-title":"Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps","volume":"73","author":"Xu","year":"2024","journal-title":"Inflammation Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/clt2.70014","article-title":"M2 macrophage derived HMOX1 defines chronic rhinosinusitis with nasal polyps","volume":"14","author":"Wang","year":"2024","journal-title":"Clin Transl Allergy"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M035352","article-title":"CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury","volume":"54","author":"Parks","year":"2013","journal-title":"J Lipid Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.263020","article-title":"Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase C\u03b4, and p38 mitogen-activated protein kinase","volume":"286","author":"Thorp","year":"2011","journal-title":"J Biol Chem"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21722","article-title":"Expression of ADAM17 and ADAM10 in nasal polyps","volume":"6","author":"Bae","year":"2016","journal-title":"Int Forum Allergy Rhinol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.179876","article-title":"MerTK-dependent efferocytosis by monocytic myeloid-derived suppressor cells mediates resolution of ischemia\/reperfusion injury after lung transplant","volume":"9","author":"Leroy","year":"2024","journal-title":"JCI Insight"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2023.2232554","article-title":"Inflammation resolution and specialized pro-resolving lipid mediators in chronic rhinosinusitis","volume":"19","author":"Robinson","year":"2023","journal-title":"Expert Rev Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2020.102218","article-title":"Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis","volume":"164","author":"Vickery","year":"2021","journal-title":"Prostaglandins Leukot Essent Fatty Acids"},{"key":"B45","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1096\/fj.201902126R","article-title":"Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage","volume":"34","author":"Rymut","year":"2020","journal-title":"FASEB J"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1524292113","article-title":"MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation","volume":"113","author":"Cai","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/alr.23542","article-title":"Mediation of LPS-induced inflammation with pro-resolving treatment in human nasal polyps: a pilot study","volume":"15","author":"Robinson","year":"2025","journal-title":"Int Forum Allergy Rhinol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021349","article-title":"Differentiation and glucocorticoid regulated apopto-phagocytic gene expression patterns in human macrophages: role of Mertk in enhanced phagocytosis","volume":"6","author":"Zahuczky","year":"2011","journal-title":"PloS One"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.12.014","article-title":"Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-\u03b4 and UCP2","volume":"1853","author":"Garabuczi","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00470-y","article-title":"Drugging the efferocytosis process: concepts and opportunities","volume":"21","author":"Mehrotra","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"B51","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/s12943-025-02484-7","article-title":"Efferocytosis: the art of cellular clearance and novel perspectives in disease therapy","volume":"24","author":"Li","year":"2025","journal-title":"Mol Cancer"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1126\/science.aai8132","article-title":"Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells","volume":"356","author":"Bosurgi","year":"2017","journal-title":"Science"},{"key":"B53","doi-asserted-by":"publisher","first-page":"194","DOI":"10.4193\/Rhin22.489","article-title":"EPOS\/EUFOREA update on indication and evaluation of biologics in chronic rhinosinusitis with nasal polyps 2023","volume":"61","author":"Fokkens","year":"2023","journal-title":"Rhinology"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31881-1","article-title":"Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials","volume":"394","author":"Bachert","year":"2019","journal-title":"Lancet"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1524315","article-title":"Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK\/Gas6 signaling in a pristane-induced lupus mouse model","volume":"16","author":"Liu","year":"2025","journal-title":"Front Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3535","article-title":"Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages","volume":"356","author":"Ip","year":"2017","journal-title":"Science"},{"key":"B57","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/nature18935","article-title":"CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis","volume":"536","author":"Kojima","year":"2016","journal-title":"Nature"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.10.005","article-title":"Clearance of apoptotic cells by lung alveolar macrophages prevents development of house dust mite-induced asthmatic lung inflammation","volume":"147","author":"Miki","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.01.014","article-title":"Blockade of the phagocytic receptor MerTK on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP","volume":"52","author":"Zhou","year":"2020","journal-title":"Immunity"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67655","article-title":"MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis","volume":"123","author":"Cook","year":"2013","journal-title":"J Clin Invest"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.01.027","article-title":"Formation of nasal polyps: the roles of innate type 2 inflammation and deposition of fibrin","volume":"145","author":"Takabayashi","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01312-0","article-title":"Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis","volume":"23","author":"Wang","year":"2022","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1938524\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:44:49Z","timestamp":1786628689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1938524\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":62,"alternative-id":["10.3389\/fimmu.2026.1938524"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1938524","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"article-number":"1938524"}}