{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:42:09Z","timestamp":1789540929454,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRK 2336 TP1, TP2, TP5, TP6; SFB1039 TPA06, B04, B06"],"award-info":[{"award-number":["GRK 2336 TP1, TP2, TP5, TP6; SFB1039 TPA06, B04, B06"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The interaction of macrophages with apoptotic cells is required for efficient resolution of inflammation. While apoptotic cell removal prevents inflammation due to secondary necrosis, it also alters the macrophage phenotype to hinder further inflammatory reactions. The interaction between apoptotic cells and macrophages is often studied by chemical or biological induction of apoptosis, which may introduce artifacts by affecting the macrophages as well and\/or triggering unrelated signaling pathways. Here, we set up a pure cell death system in which NIH 3T3 cells expressing dimerizable Caspase-8 were co-cultured with peritoneal macrophages in a transwell system. Phenotype changes in macrophages induced by apoptotic cells were evaluated by RNA sequencing, which revealed an unexpectedly dominant impact on macrophage proliferation. This was confirmed in functional assays with primary peritoneal macrophages and IC-21 macrophages. Moreover, inhibition of apoptosis during Zymosan-induced peritonitis in mice decreased mRNA levels of cell cycle mediators in peritoneal macrophages. Proliferation of macrophages in response to apoptotic cells may be important to increase macrophage numbers in order to allow efficient clearance and resolution of inflammation.<\/jats:p>","DOI":"10.3390\/ijms22052230","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T02:07:01Z","timestamp":1614132421000},"page":"2230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Apoptotic Cells induce Proliferation of Peritoneal Macrophages"],"prefix":"10.3390","volume":"22","author":[{"given":"Anne-Kathrin","family":"Knuth","sequence":"first","affiliation":[{"name":"Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstra\u00dfe 3a, 60528 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Huard","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zumer","family":"Naeem","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signaling, Department of Molecular Medicine, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rappl","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9799-7489","authenticated-orcid":false,"given":"Rebekka","family":"Bauer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina","family":"Mota","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-5259","authenticated-orcid":false,"given":"Tobias","family":"Schmid","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Fleming","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signaling, Department of Molecular Medicine, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8237-2841","authenticated-orcid":false,"given":"Bernhard","family":"Br\u00fcne","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Fulda","sequence":"additional","affiliation":[{"name":"Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstra\u00dfe 3a, 60528 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-1952","authenticated-orcid":false,"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.3389\/fimmu.2018.02586","article-title":"Factors Produced by Macrophages Eliminating Apoptotic Cells Demonstrate Pro-Resolutive Properties and Terminate Ongoing Inflammation","volume":"9","author":"Bonnefoy","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.3389\/fimmu.2020.00553","article-title":"Phagocytosis of Apoptotic Cells in Resolution of Inflammation","volume":"11","author":"Kourtzelis","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"360","DOI":"10.5483\/BMBRep.2019.52.6.140","article-title":"Metabolic influence on macrophage polarization and pathogenesis","volume":"52","author":"Thapa","year":"2019","journal-title":"BMB Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fimmu.2018.00127","article-title":"Macrophage Clearance of Apoptotic Cells: A Critical Assessment","volume":"9","author":"Gordon","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1515\/BC.2009.048","article-title":"The liaison between apoptotic cells and macrophages\u2014The end programs the beginning","volume":"390","author":"Weigert","year":"2009","journal-title":"Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1242974","DOI":"10.1126\/science.1242974","article-title":"Beyond stem cells: Self-renewal of differentiated macrophages","volume":"342","author":"Sieweke","year":"2013","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1002\/cbin.11137","article-title":"Cell death: A review of the major forms of apoptosis, necrosis and autophagy","volume":"43","year":"2019","journal-title":"Cell Biol. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/imr.12541","article-title":"Caspase-8: Regulating life and death","volume":"277","author":"Tummers","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.cub.2015.12.064","article-title":"Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages","volume":"26","author":"Fogarty","year":"2016","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.semcdb.2017.11.036","article-title":"When dying is not the end: Apoptotic caspases as drivers of proliferation","volume":"82","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1515\/hsz-2014-0164","article-title":"Inflammatory outcomes of apoptosis, necrosis and necroptosis","volume":"395","author":"Davidovich","year":"2014","journal-title":"Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1126\/science.aad0395","article-title":"RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells","volume":"350","author":"Yatim","year":"2015","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1172\/JCI92466","article-title":"Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone","volume":"128","author":"Roca","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1096\/fj.10-179473","article-title":"Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2","volume":"25","author":"Brecht","year":"2011","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-3-540-72167-3_5","article-title":"Fungal Recognition by TLR2 and Dectin-1","volume":"183","author":"Goodridge","year":"2008","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0076-6879(09)05417-2","article-title":"Chapter 17. Zymosan-induced peritonitis as a simple experimental system for the study of inflammation","volume":"461","author":"Cash","year":"2009","journal-title":"Methods Enzymol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Battistelli, M., and Falcieri, E. (2020). Apoptotic Bodies: Particular Extracellular Vesicles Involved in Intercellular Communication. Biology, 9.","DOI":"10.3390\/biology9010021"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"ra13","DOI":"10.1126\/scisignal.2000634","article-title":"Apoptotic cells activate the \u201cphoenix rising\u201d pathway to promote wound healing and tissue regeneration","volume":"3","author":"Li","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0014-5793(97)01388-4","article-title":"Prostaglandin E2 biphasic control of lymphocyte proliferation: Inhibition by picomolar concentrations","volume":"418","author":"Sergeeva","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.immuni.2018.10.011","article-title":"Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2","volume":"49","author":"Sanin","year":"2018","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ajpath.2013.10.017","article-title":"Role of CC chemokine receptor 4 in natural killer cell activation during acute cigarette smoke exposure","volume":"184","author":"Stolberg","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.smim.2016.03.016","article-title":"A stratified myeloid system, the challenge of understanding macrophage diversity","volume":"27","author":"Geissmann","year":"2015","journal-title":"Semin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Roszer, T. (2018). Understanding the Biology of Self-Renewing Macrophages. Cells, 7.","DOI":"10.3390\/cells7080103"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/imr.12224","article-title":"Tissue macrophage identity and self-renewal","volume":"262","author":"Gentek","year":"2014","journal-title":"Immunol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1038\/ncomms2877","article-title":"Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation","volume":"4","author":"Davies","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1072","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":"ref_28","doi-asserted-by":"crossref","first-page":"7226","DOI":"10.4049\/jimmunol.174.11.7226","article-title":"Fc- and complement-receptor activation stimulates cell cycle progression of macrophage cells from G1 to S","volume":"174","author":"Luo","year":"2005","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/nm.3258","article-title":"Local proliferation dominates lesional macrophage accumulation in atherosclerosis","volume":"19","author":"Robbins","year":"2013","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.biocel.2010.10.013","article-title":"TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P","volume":"43","author":"Murray","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-3-319-39406-0_9","article-title":"Killing Is Not Enough: How Apoptosis Hijacks Tumor-Associated Macrophages to Promote Cancer Progression","volume":"930","author":"Weigert","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_33","first-page":"3823","article-title":"The CD95 (APO-1\/Fas) system mediates drug-induced apoptosis in neuroblastoma cells","volume":"57","author":"Fulda","year":"1997","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neo.2018.11.002","article-title":"Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells","volume":"21","author":"Knuth","year":"2019","journal-title":"Neoplasia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Eden, E., Lipson, D., Yogev, S., and Yakhini, Z. (2007). Discovering motifs in ranked lists of DNA sequences. PLoS Comput. Biol., 3.","DOI":"10.1371\/journal.pcbi.0030039"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Eden, E., Navon, R., Steinfeld, I., Lipson, D., and Yakhini, Z. (2009). GOrilla: A tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-48"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2230\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:27:25Z","timestamp":1760160445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,24]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052230"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052230","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,24]]}}}