{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:18:59Z","timestamp":1768461539885,"version":"3.49.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Heterotrimeric G proteins of the G\u03b1i family have been implicated in signaling pathways regulating cell migration in immune diseases. The G\u03b1i-protein\u2013coupled C5a receptor is a critical regulator of IgG FcR function in experimental models of immune complex (IC)\u2013induced inflammation. By using mice deficient for G\u03b1i2 or G\u03b1i3, we show that G\u03b1i2 is necessary for neutrophil influx in skin and lung Arthus reactions and agonist-induced neutrophilia in the peritoneum, whereas G\u03b1i3 plays a less critical but variable role. Detailed analyses of the pulmonary IC-induced inflammatory response revealed several shared functions of G\u03b1i2 and G\u03b1i3, including mediating C5a anaphylatoxin receptor\u2013induced activation of macrophages, involvement in alveolar production of chemokines, transition of neutrophils from bone marrow into blood, and modulation of CD11b and CD62L expression that account for neutrophil adhesion to endothelial cells. Interestingly, C5a-stimulated endothelial polymorphonuclear neutrophil transmigration, but not chemotaxis, is enhanced versus reduced in the absence of neutrophil G\u03b1i3 or G\u03b1i2, respectively, and knockdown of endothelial G\u03b1i2 caused decreased transmigration of wild-type neutrophils. These data demonstrate that G\u03b1i2 and G\u03b1i3 contribute to inflammation by redundant, overlapping, and G\u03b1i-isoform\u2013specific mechanisms, with G\u03b1i2 exhibiting unique functions in both neutrophils and endothelial cells that appear essential for polymorphonuclear neutrophil recruitment in IC disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1201398","type":"journal-article","created":{"date-parts":[[2012,12,6]],"date-time":"2012-12-06T06:51:25Z","timestamp":1354776685000},"page":"324-333","source":"Crossref","is-referenced-by-count":30,"title":["G\u03b1i2 Is the Essential G\u03b1i Protein in Immune Complex\u2013Induced Lung Disease"],"prefix":"10.1093","volume":"190","author":[{"given":"Kristina","family":"Wiege","sequence":"first","affiliation":[{"name":"Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School , 30625 Hannover,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syed R","family":"Ali","sequence":"additional","affiliation":[{"name":"Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School , 30625 Hannover,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Gewecke","sequence":"additional","affiliation":[{"name":"Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School , 30625 Hannover,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Novakovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapy, Institute for Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University, and Interfaculty Center of Pharmacogenomic and Drug Research , 72070 T\u00fcbingen,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska M","family":"Konrad","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University , 72070 T\u00fcbingen,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Pexa","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Molecular Biology II, University Hospital and Clinics, Heinrich Heine University , 40225 D\u00fcsseldorf,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Beer-Hammer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapy, Institute for Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University, and Interfaculty Center of Pharmacogenomic and Drug Research , 72070 T\u00fcbingen,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg","family":"Reutershan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University , 72070 T\u00fcbingen,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland P","family":"Piekorz","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Molecular Biology II, University Hospital and Clinics, Heinrich Heine University , 40225 D\u00fcsseldorf,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhold E","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School , 30625 Hannover,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapy, Institute for Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University, and Interfaculty Center of Pharmacogenomic and Drug Research , 72070 T\u00fcbingen,","place":["Germany"]},{"name":"Institute for Biochemistry and Molecular Biology II, University Hospital and Clinics, Heinrich Heine University , 40225 D\u00fcsseldorf,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Engelbert","family":"Gessner","sequence":"additional","affiliation":[{"name":"Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School , 30625 Hannover,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2025032406202299700_r1","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.4049\/jimmunol.170.6.3243","article-title":"Pre-existing glomerular immune complexes induce polymorphonuclear cell recruitment through an Fc receptor-dependent respiratory burst: potential role in the perpetuation of immune nephritis","volume":"170","author":"Suzuki","year":"2003","journal-title":"J. Immunol."},{"key":"2025032406202299700_r2","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1002\/art.11237","article-title":"Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus","volume":"48","author":"Ren","year":"2003","journal-title":"Arthritis Rheum."},{"key":"2025032406202299700_r3","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.4049\/jimmunol.167.3.1601","article-title":"Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis","volume":"167","author":"Wipke","year":"2001","journal-title":"J. Immunol."},{"key":"2025032406202299700_r4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/1523-1747.ep12556058","article-title":"Neutrophil-activating proteins in psoriasis","volume":"98","author":"Schr\u00f6der","year":"1992","journal-title":"J. Invest. Dermatol."},{"key":"2025032406202299700_r5","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1164\/ajrccm.161.5.9907065","article-title":"Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis","volume":"161","author":"Pardo","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032406202299700_r6","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1172\/JCI16577","article-title":"C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease","volume":"110","author":"Shushakova","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2025032406202299700_r7","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1126\/science.273.5282.1722","article-title":"Neurogenic amplification of immune complex inflammation","volume":"273","author":"Bozic","year":"1996","journal-title":"Science"},{"key":"2025032406202299700_r8","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1172\/JCI118818","article-title":"Requirement and role of C5a in acute lung inflammatory injury in rats","volume":"98","author":"Mulligan","year":"1996","journal-title":"J. Clin. Invest."},{"key":"2025032406202299700_r9","doi-asserted-by":"crossref","first-page":"5193","DOI":"10.4049\/jimmunol.166.8.5193","article-title":"Fc \u03b3 RIII-mediated production of TNF-\u03b1 induces immune complex alveolitis independently of CXC chemokine generation","volume":"166","author":"Chouchakova","year":"2001","journal-title":"J. Immunol."},{"key":"2025032406202299700_r10","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/ilar.40.4.163","article-title":"Role and regulation of chemokines in rodent models of lung inflammation","volume":"40","author":"Czermak","year":"1999","journal-title":"ILAR J."},{"key":"2025032406202299700_r11","doi-asserted-by":"crossref","first-page":"33296","DOI":"10.1074\/jbc.M804617200","article-title":"Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation","volume":"283","author":"Konrad","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2025032406202299700_r12","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.4049\/jimmunol.135.6.4135","article-title":"Inhibition of lymphocyte and neutrophil chemotaxis by pertussis toxin","volume":"135","author":"Spangrude","year":"1985","journal-title":"J. Immunol."},{"key":"2025032406202299700_r13","first-page":"338","article-title":"The role of the cytosolic free Ca2+ transient for fMet-Leu-Phe induced actin polymerization in human neutrophils","volume":"42","author":"Bengtsson","year":"1986","journal-title":"Eur. J. Cell Biol."},{"key":"2025032406202299700_r14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/ng0695-143","article-title":"Ulcerative colitis and adenocarcinoma of the colon in G \u03b1 i2-deficient mice","volume":"10","author":"Rudolph","year":"1995","journal-title":"Nat. Genet."},{"key":"2025032406202299700_r15","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1161\/01.RES.87.10.903","article-title":"Galpha(i2) but not Galpha(i3) is required for muscarinic inhibition of contractility and calcium currents in adult cardiomyocytes","volume":"87","author":"Nagata","year":"2000","journal-title":"Circ. Res."},{"key":"2025032406202299700_r16","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1073\/pnas.0611434104","article-title":"An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver","volume":"104","author":"Gohla","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406202299700_r17","doi-asserted-by":"crossref","first-page":"439","DOI":"10.4049\/jimmunol.179.1.439","article-title":"Impaired trafficking of Gnai2+\/\u2212 and Gnai2\u2212\/\u2212 T lymphocytes: implications for T cell movement within lymph nodes","volume":"179","author":"Hwang","year":"2007","journal-title":"J. Immunol."},{"key":"2025032406202299700_r18","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.immuni.2005.01.017","article-title":"Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B cell motility within lymph node follicles","volume":"22","author":"Han","year":"2005","journal-title":"Immunity"},{"key":"2025032406202299700_r19","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1073\/pnas.0700185104","article-title":"Galphai2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation","volume":"104","author":"Pero","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406202299700_r20","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1172\/JCI12818","article-title":"Impaired activation of murine platelets lacking G alpha(i2)","volume":"108","author":"Jantzen","year":"2001","journal-title":"J. Clin. Invest."},{"key":"2025032406202299700_r21","doi-asserted-by":"crossref","first-page":"393","DOI":"10.4161\/auto.4256","article-title":"The heterotrimeric G protein G(i3) regulates hepatic autophagy downstream of the insulin receptor","volume":"3","author":"Gohla","year":"2007","journal-title":"Autophagy"},{"key":"2025032406202299700_r22","doi-asserted-by":"crossref","first-page":"980","DOI":"10.4049\/jimmunol.1200891","article-title":"Defective macrophage migration in G\u03b1i2- but not G\u03b1i3-deficient mice","volume":"189","author":"Wiege","year":"2012","journal-title":"J. Immunol."},{"key":"2025032406202299700_r23","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0076-6879(02)44721-0","article-title":"Mouse gene knockout and knockin strategies in application to alpha subunits of Gi\/Go family of G proteins","volume":"344","author":"Jiang","year":"2002","journal-title":"Methods Enzymol."},{"key":"2025032406202299700_r24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1124\/jpet.109.157230","article-title":"Modulation of alpha2-adrenoceptor functions by heterotrimeric Galphai protein isoforms","volume":"331","author":"Albarr\u00e1n-Ju\u00e1rez","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025032406202299700_r25","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1084\/jem.186.5.749","article-title":"Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor","volume":"186","author":"H\u00f6pken","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025032406202299700_r26","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.4049\/jimmunol.164.2.1065","article-title":"A codominant role of Fc \u03b3 RI\/III and C5aR in the reverse Arthus reaction","volume":"164","author":"Baumann","year":"2000","journal-title":"J. Immunol."},{"key":"2025032406202299700_r27","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.4049\/jimmunol.167.2.1022","article-title":"Distinct tissue site-specific requirements of mast cells and complement components C3\/C5a receptor in IgG immune complex-induced injury of skin and lung","volume":"167","author":"Baumann","year":"2001","journal-title":"J. Immunol."},{"key":"2025032406202299700_r28","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.4049\/jimmunol.174.5.3041","article-title":"Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G \u03b1 i2 activation that controls C5aR and Fc receptor cooperation","volume":"174","author":"Skokowa","year":"2005","journal-title":"J. Immunol."},{"key":"2025032406202299700_r29","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/eji.200939884","article-title":"Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a","volume":"39","author":"Syed","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025032406202299700_r30","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1161\/hq1201.100221","article-title":"Arg123-Tyr166 domain of human ApoA-I is critical for HDL-mediated inhibition of macrophage homing and early atherosclerosis in mice","volume":"21","author":"Holvoet","year":"2001","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025032406202299700_r31","doi-asserted-by":"crossref","first-page":"L807","DOI":"10.1152\/ajplung.00477.2004","article-title":"Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury","volume":"289","author":"Reutershan","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032406202299700_r32","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.4049\/jimmunol.179.2.1254","article-title":"Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury","volume":"179","author":"Reutershan","year":"2007","journal-title":"J. Immunol."},{"key":"2025032406202299700_r33","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1073\/pnas.96.4.1327","article-title":"Posttranslational modification of Galphao1 generates Galphao3, an abundant G protein in brain","volume":"96","author":"Exner","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406202299700_r34","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/PL00005044","article-title":"G proteins endogenously expressed in Sf 9 cells: interactions with mammalian histamine receptors","volume":"356","author":"Leopoldt","year":"1997","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"2025032406202299700_r35","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1182\/blood-2007-06-094565","article-title":"Galphai2 is required for chemokine-induced neutrophil arrest","volume":"110","author":"Zarbock","year":"2007","journal-title":"Blood"},{"key":"2025032406202299700_r36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1074-7613(00)80494-X","article-title":"Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc \u03b3 RIII (CD16) deficient mice","volume":"5","author":"Hazenbos","year":"1996","journal-title":"Immunity"},{"key":"2025032406202299700_r37","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.imlet.2005.06.022","article-title":"Fc receptors and their interaction with complement in autoimmunity","volume":"100","author":"Schmidt","year":"2005","journal-title":"Immunol. Lett."},{"key":"2025032406202299700_r38","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1165\/ajrcmb.20.4.3414","article-title":"Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB","volume":"20","author":"Lentsch","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032406202299700_r39","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1136\/thx.48.7.765","article-title":"Cytokines. 2. Cytokines and lung inflammation: mechanisms of neutrophil recruitment to the lung","volume":"48","author":"Strieter","year":"1993","journal-title":"Thorax"},{"key":"2025032406202299700_r40","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1083\/jcb.200712066","article-title":"Activation of Galphai3 triggers cell migration via regulation of GIV","volume":"182","author":"Ghosh","year":"2008","journal-title":"J. Cell Biol."},{"key":"2025032406202299700_r41","doi-asserted-by":"crossref","first-page":"9547","DOI":"10.1074\/jbc.M610931200","article-title":"Inhibition of G alpha i2 activation by G alpha i3 in CXCR3-mediated signaling","volume":"282","author":"Thompson","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2025032406202299700_r42","doi-asserted-by":"crossref","first-page":"14475","DOI":"10.1073\/pnas.1936026100","article-title":"Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through \u03b2 2-adrenoceptors","volume":"100","author":"Foerster","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406202299700_r43","doi-asserted-by":"crossref","first-page":"e24979","DOI":"10.1371\/journal.pone.0024979","article-title":"G\u03b1i2- and G\u03b1i3-specific regulation of voltage-dependent L-type calcium channels in cardiomyocytes","volume":"6","author":"Dizayee","year":"2011","journal-title":"PLoS ONE"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/190\/1\/324\/61773322\/1201398.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/190\/1\/324\/61773322\/1201398.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T23:08:27Z","timestamp":1742944107000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/190\/1\/324\/8003066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,1]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1201398","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,1]]},"published":{"date-parts":[[2013,1,1]]}}}