{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T02:34:15Z","timestamp":1790217255092,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wilhelm and Martina Lundgrens foundation","award":["2017-1593"],"award-info":[{"award-number":["2017-1593"]}]},{"name":"Gothenburg Society of Medicine Foundation","award":["GLS-888161"],"award-info":[{"award-number":["GLS-888161"]}]},{"DOI":"10.13039\/501100001034","name":"Swedish government and the county councils","doi-asserted-by":"publisher","award":["ALFGBG-77860"],"award-info":[{"award-number":["ALFGBG-77860"]}],"id":[{"id":"10.13039\/501100001034","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001034","name":"Swedish government and the county councils","doi-asserted-by":"publisher","award":["ALFGBG-75710"],"award-info":[{"award-number":["ALFGBG-75710"]}],"id":[{"id":"10.13039\/501100001034","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001034","name":"Swedish government and the county councils","doi-asserted-by":"publisher","award":["ALFGBG-965174"],"award-info":[{"award-number":["ALFGBG-965174"]}],"id":[{"id":"10.13039\/501100001034","id-type":"DOI","asserted-by":"publisher"}]},{"name":"VR","award":["2019-01320"],"award-info":[{"award-number":["2019-01320"]}]},{"name":"VR","award":["2023-02035"],"award-info":[{"award-number":["2023-02035"]}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["2021-0056"],"award-info":[{"award-number":["2021-0056"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Brain damage caused by hypoxia-ischemia is a serious complication for a newborn with possible life-long sequelae. To develop targeted neuroprotective strategies, it is essential to understand the mechanisms of injury, particularly the role of microglial phagocytosis, which may contribute to neuronal loss after hypoxia-ischemia. The aim was to evaluate neuronal cell death by phagocytosis in neonatal hypoxia-ischemia by investigating key signaling molecules and the effect of gene deletion of the phagocytic receptor Myeloid-epithelial-reproductive tyrosine kinase (MerTK) in a neonatal mouse model. MerTK, growth arrest\u2013specific 6, and genes related to phagoptosis were regulated in the brain 6\u201372 h after hypoxic ischemia. Brain injury was reduced in MerTK knock-out vs. wild-type mice by 48% in gray matter (p = 0.002) and by 32% in white matter (p = 0.04). There was a near 40% reduction in NeuN immunoreactivity in microglia in MerTK knock-out mice vs. wild-type (p = 0.03) indicating attenuation of neuronal phagocytosis by microglia. In summary, the reduction in microglial neuronal engulfment and brain injury in MerTK-deficient mice strongly indicates that phagoptosis contributes to neuronal loss after neonatal hypoxia-ischemia. This insight suggests that targeting MerTK-mediated phagocytosis may represent a potential therapeutic approach in neonatal hypoxia-ischemic brain injury.<\/jats:p>","DOI":"10.3390\/cells14231862","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:04:57Z","timestamp":1764151497000},"page":"1862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MerTK and the Role of Phagoptosis in Neonatal Hypoxia-Ischemia"],"prefix":"10.3390","volume":"14","author":[{"given":"Andrea","family":"Jonsdotter","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, 416 85 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-1448","authenticated-orcid":false,"given":"Henrik","family":"Hagberg","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, 416 85 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"Leverin","sequence":"additional","affiliation":[{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Ek","sequence":"additional","affiliation":[{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-183X","authenticated-orcid":false,"given":"Kerstin","family":"Ebefors","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-4691","authenticated-orcid":false,"given":"Eridan","family":"Rocha-Ferreira","sequence":"additional","affiliation":[{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1414-7279","authenticated-orcid":false,"given":"Ylva","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, 416 85 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"},{"name":"Centre of Perinatal Medicine & Health, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, V\u00e4stra G\u00f6taland, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.nbd.2015.09.011","article-title":"Perinatal brain damage: The term infant","volume":"92 Pt A","author":"Hagberg","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1056\/NEJMoa1315788","article-title":"Effects of hypothermia for perinatal asphyxia on childhood outcomes","volume":"371","author":"Azzopardi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1273","DOI":"10.1016\/S2214-109X(21)00264-3","article-title":"Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): A randomised controlled trial in India, Sri Lanka, and Bangladesh","volume":"9","author":"Thayyil","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1002\/jnr.24761","article-title":"White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia","volume":"99","author":"Shao","year":"2021","journal-title":"J. Neurosci. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5910","DOI":"10.1523\/JNEUROSCI.22-14-05910.2002","article-title":"Interleukin-18 involvement in hypoxic-ischemic brain injury","volume":"22","author":"Leverin","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0165-3806(94)00177-2","article-title":"Microglia activation after neonatal hypoxic-ischemia","volume":"84","author":"McRae","year":"1995","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1203\/00006450-199610000-00015","article-title":"Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats","volume":"40","author":"Hagberg","year":"1996","journal-title":"Pediatr. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Brown, G.C. (2021). Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413442"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1007\/s12035-013-8620-6","article-title":"Phagocytosis of microglia in the central nervous system diseases","volume":"49","author":"Fu","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nrn3710","article-title":"Microglial phagocytosis of live neurons","volume":"15","author":"Brown","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41577-023-00921-6","article-title":"Cell death by phagocytosis","volume":"24","author":"Brown","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E4098","DOI":"10.1073\/pnas.1308679110","article-title":"Phagocytosis executes delayed neuronal death after focal brain ischemia","volume":"110","author":"Neher","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/s12974-021-02280-2","article-title":"Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y(6) receptor in mice","volume":"18","author":"Milde","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.tibs.2012.05.002","article-title":"Eaten alive! Cell death by primary phagocytosis: \u2018phagoptosis\u2019","volume":"37","author":"Brown","year":"2012","journal-title":"Trends Biochem. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2212646120","DOI":"10.1073\/pnas.2212646120","article-title":"Microglia phagocytosis mediates the volume and function of the rat sexually dimorphic nucleus of the preoptic area","volume":"120","author":"Pickett","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/ana.410090206","article-title":"The influence of immaturity on hypoxic-ischemic brain damage in the rat","volume":"9","author":"Rice","year":"1981","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1159\/000047087","article-title":"Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia","volume":"79","author":"Wang","year":"2001","journal-title":"Biol. Neonate"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Webster, C.M., Hokari, M., McManus, A., Tang, X.N., Ma, H., Kacimi, R., and Yenari, M.A. (2013). Microglial P2Y12 deficiency\/inhibition protects against brain ischemia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070927"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0165-5728(02)00033-4","article-title":"Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury","volume":"125","author":"Soriano","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cockram, T.O.J., Dundee, J.M., Popescu, A.S., and Brown, G.C. (2021). The Phagocytic Code Regulating Phagocytosis of Mammalian Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.629979"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sapkota, A., Gaire, B.P., Kang, M.G., and Choi, J.W. (2019). S1P(2) contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1\/2 and JNK. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-48609-z"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.7150\/thno.35841","article-title":"Microglia exacerbate white matter injury via complement C3\/C3aR pathway after hypoperfusion","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/glia.21110","article-title":"Osteopontin: Correlation with phagocytosis by brain macrophages in a rat model of stroke","volume":"59","author":"Shin","year":"2011","journal-title":"Glia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1523\/JNEUROSCI.3830-11.2012","article-title":"Sialic acid on the neuronal glycocalyx prevents complement C1 binding and complement receptor-3-mediated removal by microglia","volume":"32","author":"Linnartz","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1177\/0271678X18817282","article-title":"Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke","volume":"39","author":"Kurisu","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/glia.22693","article-title":"Inhibition of UDP\/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo","volume":"62","author":"Neher","year":"2014","journal-title":"Glia"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Li, H., Li, X., Wu, J., Xue, T., Wu, J., Shen, H., Shen, M., and Chen, G. (2020). TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01144"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/cns.13620","article-title":"Microglial\/Macrophage polarization and function in brain injury and repair after stroke","volume":"27","author":"Lyu","year":"2021","journal-title":"CNS Neurosci. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nrneurol.2015.13","article-title":"The role of inflammation in perinatal brain injury","volume":"11","author":"Hagberg","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.bbrc.2019.11.003","article-title":"The role of microglia mediated pyroptosis in neonatal hypoxic-ischemic brain damage","volume":"521","author":"Lv","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S1474-4422(13)70261-8","article-title":"Mitochondria: Hub of injury responses in the developing brain","volume":"13","author":"Hagberg","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1097\/00001756-199710200-00033","article-title":"Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins","volume":"8","author":"Thoresen","year":"1997","journal-title":"Neuroreport"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000046143","article-title":"Oxidant mechanisms in neonatal hypoxia-ischemia","volume":"23","author":"Ferriero","year":"2001","journal-title":"Dev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1203\/pdr.0b013e3180332be4","article-title":"Global gene expression in the developing rat brain after hypoxic preconditioning: Involvement of apoptotic mechanisms?","volume":"61","author":"Gustavsson","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39728","DOI":"10.1074\/jbc.M204619200","article-title":"Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance","volume":"277","author":"Bernaudin","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12974-016-0581-z","article-title":"Brain trauma elicits non-canonical macrophage activation states","volume":"13","author":"Kim","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8686","DOI":"10.1073\/pnas.0500419102","article-title":"The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription","volume":"102","author":"Murray","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s12974-016-0762-9","article-title":"Inhibition of STAT3- and MAPK-dependent PGE(2) synthesis ameliorates phagocytosis of fibrillar \u03b2-amyloid peptide (1-42) via EP2 receptor in EMF-stimulated N9 microglial cells","volume":"13","author":"He","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3806","DOI":"10.1093\/brain\/awz319","article-title":"Decreased microglial Wnt\/\u03b2-catenin signalling drives microglial pro-inflammatory activation in the developing brain","volume":"142","author":"Schang","year":"2019","journal-title":"Brain"}],"updated-by":[{"DOI":"10.3390\/cells15070621","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000}}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T08:17:37Z","timestamp":1774945057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14231862"],"URL":"https:\/\/doi.org\/10.3390\/cells14231862","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}