{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:56:56Z","timestamp":1792263416647,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T00:00:00Z","timestamp":1643414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY030076"],"award-info":[{"award-number":["EY030076"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Inflammation is increasingly recognized as an important modulator in the pathogenesis of neovascular age-related macular degeneration (nAMD). Although significant progress has been made in delineating the pathways that contribute to the recruitment of inflammatory cells and their contribution to nAMD, we know little about what drives the resolution of these inflammatory responses. Gaining a better understanding of how immune cells are cleared in the choroid will give a novel insight into how sustained inflammation could influence the pathogenesis of nAMD. The pro-apoptotic Bcl-2 family member Bim is a master regulator of immune cell homeostasis. In its absence, immune cell lifespan and numbers increase. Most therapeutic regimes that squelch inflammation do so by enhancing immune cell apoptosis through enhanced Bim expression and activity. To test the hypothesis that Bim expression tempers inflammation during the pathogenesis of nAMD, we used the mouse laser-induced choroidal neovascularization (CNV) model in which inflammation acts as a facilitator of CNV. Here, we showed minimal to no change in the recruitment of F4\/80-, CD80-, CD11b-, and Iba1-positive myeloid-derived mononuclear phagocytes to the site of laser photocoagulation in the absence of Bim expression. However, the resolution of these cells from the choroid of Bim-deficient (Bim -\/-) mice was significantly diminished following laser photocoagulation. With time, we noted increased scar formation, demonstrated by collagen I staining, in Bim -\/- mice with no change in the resolution of neovascularization compared to wild-type littermates. We also noted that mice lacking Bim expression in mononuclear phagocytes (BimFlox\/Flox; Lyz2-Cre (BimMP) mice) had delayed resolution of F4\/80-, CD80-, CD11b-, and Iba1-positive cells, while those lacking Bim expression in endothelial cells (BimFlox\/Flox; Cad5-Cre (BimEC) mice) had delayed resolution of only CD11b- and Iba1-positive cells. Both BimMP and BimEC mice demonstrated increased scar formation, albeit to differing degrees. Thus, our studies show that resolving inflammation plays an important role in moderating scar formation in nAMD, and it is impacted by Bim expression in both the endothelium and mononuclear phagocyte lineages.<\/jats:p>","DOI":"10.3390\/life12020208","type":"journal-article","created":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:12:56Z","timestamp":1643501576000},"page":"208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bim Expression Promotes the Clearance of Mononuclear Phagocytes during Choroidal Neovascularization, Mitigating Scar Formation in Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Shoujian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail S.","family":"Zaitoun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soesiawati R.","family":"Darjatmoko","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-9217","authenticated-orcid":false,"given":"Nader","family":"Sheibani","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Sorenson","sequence":"additional","affiliation":[{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1056\/NEJMra0801537","article-title":"Age-related macular degeneration","volume":"358","author":"Jager","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3129\/i08-049","article-title":"Ocular blood flow in diabetes and age-related macular degeneration","volume":"43","author":"Pemp","year":"2008","journal-title":"Can. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1042\/CS20170066","article-title":"Negative regulators of angiogenesis: Important targets for treatment of exudative amd","volume":"131","author":"Farnoodian","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/380435a0","article-title":"Abnormal blood vessel development and lethality in embryos lacking a single vegf allele","volume":"380","author":"Carmeliet","year":"1996","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/380439a0","article-title":"Heterozygous embryonic lethality induced by targeted inactivation of the vegf gene","volume":"380","author":"Ferrara","year":"1996","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.4049\/jimmunol.171.5.2652","article-title":"Immunoregulatory role of ocular macrophages: The macrophages produce rantes to suppress experimental autoimmune uveitis","volume":"171","author":"Sonoda","year":"2003","journal-title":"J. Immunol."},{"key":"ref_7","first-page":"503725","article-title":"Infiltration of proinflammatory m1 macrophages into the outer retina precedes damage in a mouse model of age-related macular degeneration","volume":"2013","author":"Saeed","year":"2013","journal-title":"Int. J. Inflamm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/emmm.201302692","article-title":"Ccr2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in cx3cr1 deficient mice","volume":"5","author":"Sennlaub","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1189\/jlb.0902436","article-title":"The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization","volume":"74","author":"Tsutsumi","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1001\/archopthalmol.2011.1892","article-title":"Lack of thrombospondin 1 and exacerbation of choroidal neovascularization","volume":"130","author":"Wang","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.ydbio.2010.10.034","article-title":"Bim is responsible for the inherent sensitivity of the developing retinal vasculature to hyperoxia","volume":"349","author":"Wang","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, S., Zaitoun, I.S., Johnson, R.P., Jamali, N., Gurel, Z., Wintheiser, C.M., Strasser, A., Lindner, V., Sheibani, N., and Sorenson, C.M. (2017). Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178198"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3389\/fped.2016.00135","article-title":"Killing two cells with one stone: Pharmacologic bcl-2 family targeting for cancer cell death and immune modulation","volume":"4","author":"Ludwig","year":"2016","journal-title":"Front. Pediatrics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1446","DOI":"10.1038\/cddis.2014.409","article-title":"Impact of conditional deletion of the pro-apoptotic bcl-2 family member bim in mice","volume":"5","author":"Herold","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/sj.cdd.4401537","article-title":"Proapoptotic bcl-2 family member bim is involved in the control of mast cell survival and is induced together with bcl-xl upon ige-receptor activation","volume":"12","author":"Alfredsson","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1084\/jem.20170479","article-title":"Bim suppresses the development of sle by limiting myeloid inflammatory responses","volume":"214","author":"Tsai","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1182\/blood-2013-01-478206","article-title":"Local apoptosis mediates clearance of macrophages from resolving inflammation in mice","volume":"122","author":"Gautier","year":"2013","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1242\/jcs.018036","article-title":"Integrin-dependent phagocytosis: Spreading from microadhesion to new concepts","volume":"121","author":"Dupuy","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI88442","article-title":"Cd11b activation suppresses tlr-dependent inflammation and autoimmunity in systemic lupus erythematosus","volume":"127","author":"Faridi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/ni.1908","article-title":"Integrin cd11b negatively regulates tlr-triggered inflammatory responses by activating syk and promoting degradation of myd88 and trif via cbl-b","volume":"11","author":"Han","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/ni0810-691","article-title":"Integrins limit the toll","volume":"11","author":"Means","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1084\/jem.20060925","article-title":"Intraluminal crawling of neutrophils to emigration sites: A molecularly distinct process from adhesion in the recruitment cascade","volume":"203","author":"Phillipson","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S0955-0674(97)80117-2","article-title":"Leukocyte adhesion: Cd11\/cd18 integrins and intercellular adhesion molecules","volume":"9","author":"Gahmberg","year":"1997","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6965","DOI":"10.1158\/0008-5472.CAN-11-0588","article-title":"Combined blockade of integrin-\u03b14\u03b21 plus cytokines sdf-1\u03b1 or il-1\u03b2 potently inhibits tumor inflammation and growth","volume":"71","author":"Schmid","year":"2011","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.4049\/jimmunol.164.12.6166","article-title":"M-1\/m-2 macrophages and the th1\/th2 paradigm","volume":"164","author":"Mills","year":"2000","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12974-015-0422-5","article-title":"Targeting translocator protein (18 kda) (tspo) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration","volume":"12","author":"Scholz","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_28","first-page":"354","article-title":"Microglial activation and chronic neurodegeneration","volume":"7","author":"Lull","year":"2010","journal-title":"Neurother. J. Am. Soc. Exp. Neurother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"671","DOI":"10.4049\/jimmunol.174.2.671","article-title":"Phagocytosis-induced apoptosis in macrophages is mediated by up-regulation and activation of the bcl-2 homology domain 3-only protein bim","volume":"174","author":"Kirschnek","year":"2005","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/art.27198","article-title":"Bim-bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis","volume":"62","author":"Scatizzi","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature09982","article-title":"Non-apoptotic role of bid in inflammation and innate immunity","volume":"474","author":"Yeretssian","year":"2011","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S168","DOI":"10.1038\/onc.2009.54","article-title":"Bh3-only proteins in rheumatoid arthritis: Potential targets for therapeutic intervention","volume":"27","author":"Hutcheson","year":"2008","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.immuni.2007.12.015","article-title":"Combined deficiency of proapoptotic regulators bim and fas results in the early onset of systemic autoimmunity","volume":"28","author":"Hutcheson","year":"2008","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.4049\/jimmunol.169.6.3006","article-title":"Bcl-2 controls dendritic cell longevity in vivo","volume":"169","author":"Nopora","year":"2002","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/ni1071","article-title":"A bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells","volume":"5","author":"Hou","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6941","DOI":"10.4049\/jimmunol.180.10.6941","article-title":"Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock","volume":"180","author":"Gautier","year":"2008","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"671989","DOI":"10.3389\/fcell.2021.671989","article-title":"Targeted thrombospondin-1 expression in ocular vascular development and neovascularization","volume":"9","author":"Sorenson","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Augis, V., Airiau, K., Josselin, M., Turcq, B., Mahon, F.X., and Belloc, F. (2013). A single nucleotide polymorphism in cbim is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078582"},{"key":"ref_39","first-page":"33","article-title":"Influence of bcl2l11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia","volume":"19","author":"Plesa","year":"2019","journal-title":"Pharm. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"68933","DOI":"10.18632\/oncotarget.12112","article-title":"Bim deletion polymorphisms in hispanic patients with non-small cell lung cancer carriers of egfr mutations","volume":"7","author":"Cardona","year":"2016","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11348","DOI":"10.1038\/srep11348","article-title":"The effect of bim deletion polymorphism on intrinsic resistance and clinical outcome of cancer patient with kinase inhibitor therapy","volume":"5","author":"Ying","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/dvdy.20643","article-title":"Ve-cadherin-cre-recombinase transgenic mouse: A tool for lineage analysis and gene deletion in endothelial cells","volume":"235","author":"Alva","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.devcel.2010.05.006","article-title":"The wnt\/beta-catenin pathway modulates vascular remodeling and specification by upregulating dll4\/notch signaling","volume":"18","author":"Corada","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/dvg.20769","article-title":"Characterization of pdgfrb-cre transgenic mice reveals reduction of rosa26 reporter activity in remodeling arteries","volume":"49","author":"Cuttler","year":"2011","journal-title":"Genesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1096\/fj.13-228551","article-title":"Crosstalk between the equilibrative nucleoside transporter ent2 and alveolar adora2b adenosine receptors dampens acute lung injury","volume":"27","author":"Eckle","year":"2013","journal-title":"FASEB J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nm.1947","article-title":"Histone h2ax is integral to hypoxia-driven neovascularization","volume":"15","author":"Economopoulou","year":"2009","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1242\/dev.084871","article-title":"Endothelial deletion of murine jag1 leads to valve calcification and congenital heart defects associated with alagille syndrome","volume":"139","author":"Hofmann","year":"2012","journal-title":"Development"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"353","DOI":"10.4097\/kja.d.18.00242","article-title":"What is the proper way to apply the multiple comparison test?","volume":"71","author":"Lee","year":"2018","journal-title":"Korean J. Anesthesiol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/2\/208\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:10:49Z","timestamp":1760134249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/2\/208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,29]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["life12020208"],"URL":"https:\/\/doi.org\/10.3390\/life12020208","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,29]]}}}