TY - JOUR
T1 - Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury
AU - Sahu, Sanjaya K.
AU - Ozantürk, Ayşe N.
AU - Kulkarni, Devesha H.
AU - Ma, Lina
AU - Barve, Ruteja A.
AU - Dannull, Linus
AU - Lu, Angel
AU - Starick, Marick
AU - McPhatter, Ja'Nia
AU - Garnica, Lorena
AU - Sanfillipo-Burchman, Maxwell
AU - Kunen, Jeremy
AU - Wu, Xiaobo
AU - Gelman, Andrew E.
AU - Brody, Steven L.
AU - Atkinson, John P.
AU - Kulkarni, Hrishikesh S.
N1 - Funding Information:
Acknowledgments:W ethankC.Kemper,D.Hourcade,J.Haspel,M.Holtzman,J.Koenitzer, and Y .-C. Perng for insights on the work and contribution of reagents. W e thank L. Mitchell, K.Liszewski,C.Gierasch,J.Xu,J.-H.Pan,S.Gunsten,T .Huang,C.Min,andA.Pesaventofor technical assistance. Funding: This research was financed by the National Heart, Lung, and BloodInstituteoftheNIH(grantK08HL148510toH.S.K.);NationalInstituteofGeneralMedical SciencesoftheNIH(grantR35GM136352toJ.P .A.); NationalEyeInstituteoftheNIH(grant R01EYE028602 to J.P .A.); Children’s Discovery Institute (to H.S.K.); Rheumatic Diseases Research Resource-BasedCenter(projectnumberP30AR073752toH.S.K.);theClarkFamily/Clayco FoundationInternationalCerebroretinalVasculopathy(CRV)ResearchA ward(toJ.P .A.); andthe FoundationforBarnes-JewishHospital(toS.L.B.).Experimentalsupportwasalsopartially providedbytheBurskyCenterforHumanImmunologyandImmunotherapyProgramsat W ashington UniversityImmunomonitoringLaboratory,insupportoftheRheumaticDiseases CoreCenter(projectnumberNIHWLC6313040077).Authorcontributions:Conceptualization: H.S.K.,S.L.B.,andJ.P .A. Methodology:A.N.O.,D.H.K.,S.K.S.,L.D.,M.S.,L.M.,J.M.,L.G.,J.K.,andX.W . Investiga tion: H.S.K.,A.N.O.,D.H.K.,L.D.,A.L.,M.S.,andS.K.S.Visualization:H.S.K.,A.N.O.,D.H.K., L.D.,M.S.,R.A.B.,andS.K.S.Fundingacquisition:H.S.K.andJ.P .A. Projectadministration:H.S.K. Supervision:H.S.K.andJ.P .A. Writing(originaldraft):H.S.K.,A.N.O.,S.K.S.,R.A.B.,J.P .A., andS.L.B. Writing(reviewandediting):H.S.K.,A.N.O.,D.H.K.,R.A.B.,S.K.S.,L.D.,A.L.,M.S.,M.S.-B.,L.M.,J.M., L.G., J.K., X.W ., A.E.G., J.P .A., and S.L.B. Competing interests: H.S.K. reports receiving grant fundingforAlexionPharmaceuticalsunrelatedtothesubmittedwork.H.S.K.reportsservingas apaidconsultantforGuidepointGlobalAdvisorsandArrowheadPharmaceuticals.J.P .A. reports servingasaconsultantforCelldexTherapeutics,ClinicalPharmacyServices,KyphaInc., AchillionPharmaceuticalsInc.,andBioMarinPharmaceuticalInc.J.P .A. hasstockorequity optionsinComplimentCorporation,KyphaInc.,GeminiTherapeutics,andQ32Bio.S.L.B.has receivedlaboratoryresearchfundsfromGenentech.R.A.B.mayreceiveroyaltyincomebasedon theCOMPBIOmethoddevelopedbyR.A.B.andlicensedbyW ashington UniversitytoPercayAI. Theotherauthorsdeclarethattheyhavenocompetinginterests.Dataandmaterials availability:TheRNA-seqdatasethasbeendepositedonNCBIGEO[www.ncbi.nlm.nih.gov/ geo/ (GSE218554)]. All other data needed to evaluate the reported conclusions are present in thepaperortheSupplementaryMaterials.
Funding Information:
This research was financed by the National Heart, Lung, and Blood Institute of the NIH (grant K08HL148510 to H.S.K.); National Institute of General Medical Sciences of the NIH (grant R35GM136352 to J.P.A.); National Eye Institute of the NIH (grant R01EYE028602 to J.P.A.); Children’s Discovery Institute (to H.S.K.); Rheumatic Diseases Research Resource-Based Center (project number P30AR073752 to H.S.K.); the Clark Family/Clayco Foundation International Cerebroretinal Vasculopathy (CRV) Research Award (to J.P.A.); and the Foundation for Barnes-Jewish Hospital (to S.L.B.). Experimental support was also partially provided by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University Immunomonitoring Laboratory, in support of the Rheumatic Diseases Core Center (project number NIH WLC6313040077).
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023/2
Y1 - 2023/2
N2 - The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa. Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.
AB - The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa. Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.
UR - http://www.scopus.com/inward/record.url?scp=85147457834&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.abp9547
DO - 10.1126/sciimmunol.abp9547
M3 - Article
C2 - 36735773
AN - SCOPUS:85147457834
SN - 2470-9468
VL - 8
JO - Science immunology
JF - Science immunology
IS - 80
M1 - eabp9547
ER -