Single-Cell Transcriptomics Reveals Compartment-Specific Differences in Immune Responses and Contributions for Complement Factor 3 in Hemorrhagic Shock Plus Tissue Trauma.
Journal
Shock (Augusta, Ga.)
ISSN: 1540-0514
Titre abrégé: Shock
Pays: United States
ID NLM: 9421564
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
pubmed:
13
3
2021
medline:
18
3
2022
entrez:
12
3
2021
Statut:
ppublish
Résumé
Hemorrhagic shock with tissue trauma (HS/T) leads to the activation of a system-wide immune-inflammatory response that involves all organs and body compartments. Recent advances in single-cell analysis permit the simultaneous assessment of transcriptomic patterns in a large number of cells making it feasible to survey the landscape of immune cell responses across numerous anatomic sites. Here, we used single-cell RNA sequencing of leukocytes from the blood, liver, and spleen to identify the major shifts in gene expression by cell type and compartment in a mouse HS/T model. At 6 h, dramatic changes in gene expression were observed across multiple-cell types and in all compartments in wild-type mice. Monocytes from circulation and liver exhibited a significant upregulation of genes associated with chemotaxis and migration and a simultaneous suppression of genes associated with interferon signaling and antigen presentation. In contrast, liver conventional DC exhibited a unique pattern compared with other myeloid cells that included a pronounced increase in major histocompatibility complex class II (MHCII) gene expression. The dominant pattern across all compartments for B and T cells was a suppression of genes associated with cell activation and signaling after HS/T. Using complement factor 3 (C3) knockout mice we unveiled a role for C3 in the suppression of monocyte Major Histocompatibility Complex class II expression and activation of gene expression associated with migration, phagocytosis and cytokine upregulation, and an unexpected role in promoting interferon-signaling in a subset of B and T cells across all three compartments after HS/T. This transcriptomic landscape study of immune cells provides new insights into the host immune response to trauma, as well as a rich resource for further investigation of trauma-induced immune responses and complement in driving interferon signaling.
Identifiants
pubmed: 33710107
doi: 10.1097/SHK.0000000000001765
pii: 00024382-202112000-00017
pmc: PMC8429528
mid: NIHMS1692565
doi:
Substances chimiques
Complement C3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
994-1008Subventions
Organisme : NIAID NIH HHS
ID : R01 AI152044
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM127027
Pays : United States
Organisme : NHLBI NIH HHS
ID : R38 HL150207
Pays : United States
Informations de copyright
Copyright © 2021 by the Shock Society.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest.
Références
Bortolotti P, Faure E, Kipnis E. Inflammasomes in tissue damages and immune disorders after trauma. Front Immunol 9:1900, 2018.
Cuenca AG, Maier RV, Cuschieri J, Moore EE, Moldawer LL, Tompkins RG. Inflammation, host response to injury LSCRP: the Glue Grant experience: characterizing the post injury genomic response. Eur J Trauma Emerg Surg 37 (6):549–558, 2011.
Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, Hayden DL, Hennessy L, Moore EE, Minei JP, et al. A genomic storm in critically injured humans. J Exp Med 208 (13):2581–2590, 2011.
Cabrera CP, Manson J, Shepherd JM, Torrance HD, Watson D, Longhi MP, Hoti M, Patel MB, O’Dwyer M, Nourshargh S, et al. Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: a prospective cohort study. PLoS Med 14 (7):e1002352, 2017.
Grun D, van Oudenaarden A. Design and analysis of single-cell sequencing experiments. Cell 163 (4):799–810, 2015.
Papalexi E, Satija R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol 18 (1):35–45, 2018.
Chen T, Delano MJ, Chen K, Sperry JL, Namas RA, Lamparello AJ, Deng M, Conroy J, Moldawer LL, Efron PA, et al. A roadmap from single-cell transcriptome to patient classification for the immune response to trauma. JCI Insight 6:145108, 2021.
Karasu E, Nilsson B, Kohl J, Lambris JD, Huber-Lang M. Targeting complement pathways in polytrauma- and sepsis-induced multiple-organ dysfunction. Front Immunol 10:543, 2019.
Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11 (9):785–797, 2010.
Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol 19 (4):327–341, 2018.
Hecke F, Schmidt U, Kola A, Bautsch W, Klos A, Kohl J. Circulating complement proteins in multiple trauma patients—correlation with injury severity, development of sepsis, and outcome. Crit Care Med 25 (12):2015–2024, 1997.
Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, Bruckner U, Stahl GL, Blom AM, Perl M, et al. Early complementopathy after multiple injuries in humans. Shock 37 (4):348–354, 2012.
Ganter MT, Brohi K, Cohen MJ, Shaffer LA, Walsh MC, Stahl GL, Pittet JF. Role of the alternative pathway in the early complement activation following major trauma. Shock 28 (1):29–34, 2007.
Chakraborty S, Karasu E, Huber-Lang M. Complement after trauma: suturing innate and adaptive immunity. Front Immunol 9:2050, 2018.
Hawksworth OA, Coulthard LG, Woodruff TM. Complement in the fundamental processes of the cell. Mol Immunol 84:17–25, 2017.
Atefi G, Aisiku O, Shapiro N, Hauser C, Dalle Lucca J, Flaumenhaft R, Tsokos GC. Complement activation in trauma patients alters platelet function. Shock 46: (3 suppl 1): 83–88, 2016.
Cai C, Gill R, Eum HA, Cao Z, Loughran PA, Darwiche S, Edmonds RD, Menzel CL, Billiar TR. Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome. Am J Physiol Regul Integr Comp Physiol 299 (5):R1175–1182, 2010.
Chen D, Song MQ, Liu YJ, Xue YK, Cheng P, Zheng H, Chen LB. Inhibition of complement C3 might rescue vascular hyporeactivity in a conscious hemorrhagic shock rat model. Microvasc Res 105:23–29, 2016.
Huber-Lang M, Gebhard F, Schmidt CQ, Palmer A, Denk S, Wiegner R. Complement therapeutic strategies in trauma, hemorrhagic shock and systemic inflammation—closing Pandora's box? Semin Immunol 28 (3):278–284, 2016.
van Griensven M, Ricklin D, Denk S, Halbgebauer R, Braun CK, Schultze A, Hones F, Koutsogiannaki S, Primikyri A, Reis E, et al. Protective effects of the complement inhibitor compstatin CP40 in hemorrhagic shock. Shock 51 (1):78–87, 2019.
DiMaggio C, Ayoung-Chee P, Shinseki M, Wilson C, Marshall G, Lee DC, Wall S, Maulana S, Leon Pachter H, Frangos S. Traumatic injury in the United States: in-patient epidemiology 2000-2011. Injury 47 (7):1393–1403, 2016.
Kohut LK, Darwiche SS, Brumfield JM, Frank AM, Billiar TR. Fixed volume or fixed pressure: a murine model of hemorrhagic shock. J Vis Exp 2011; (52):2068.
Darwiche SS, Kobbe P, Pfeifer R, Kohut L, Pape HC, Billiar T. Pseudofracture: an acute peripheral tissue trauma model. J Vis Exp 2011; (50):2074.
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36 (5):411–420, 2018.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16 (5):284–287, 2012.
Chen S, Hoffman RA, Scott M, Manson J, Loughran P, Ramadan M, Demetris AJ, Billiar TR. NK1.1(+) cells promote sustained tissue injury and inflammation after trauma with hemorrhagic shock. J Leukoc Biol 102 (1):127–134, 2017.
Heftrig D, Sturm R, Oppermann E, Kontradowitz K, Jurida K, Schimunek L, Woschek M, Marzi I, Relja B. Impaired surface expression of HLA-DR, TLR2, TLR4, and TLR9 in ex vivo-in vitro stimulated monocytes from severely injured trauma Patients. Mediators Inflamm 2017:2608349, 2017.
Bottini N, Peterson EJ. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol 32:83–119, 2014.
Liu C, Richard K, Wiggins M, Zhu X, Conrad DH, Song W. CD23 can negatively regulate B-cell receptor signaling. Sci Rep 6:25629, 2016.
Dho SH, Lim JC, Kim LK. Beyond the role of CD55 as a complement component. Immune Netw 18 (1):e11, 2018.
Yokoyama K, Su Ih IH, Tezuka T, Yasuda T, Mikoshiba K, Tarakhovsky A, Yamamoto T. BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor. EMBO J 21 (1–2):83–92, 2002.
Georg I, Diaz-Barreiro A, Morell M, Pey AL, Alarcon-Riquelme ME. BANK1 interacts with TRAF6 and MyD88 in innate immune signaling in B cells. Cell Mol Immunol 17 (9):954–965, 2020.
Tolar P. Cytoskeletal control of B cell responses to antigens. Nat Rev Immunol 17 (10):621–634, 2017.
Zhang Y, Zhang J, Korff S, Ayoob F, Vodovotz Y, Billiar TR. Delayed neutralization of interleukin 6 reduces organ injury, selectively suppresses inflammatory mediator, and partially normalizes immune dysfunction following trauma and hemorrhagic shock. Shock 42 (3):218–227, 2014.
Manfredi AA, Capobianco A, Bianchi ME, Rovere-Querini P. Regulation of dendritic- and T-cell fate by injury-associated endogenous signals. Crit Rev Immunol 29 (1):69–86, 2009.
Ruan X, Darwiche SS, Cai C, Scott MJ, Pape HC, Billiar TR. Anti-HMGB1 monoclonal antibody ameliorates immunosuppression after peripheral tissue trauma: attenuated T-lymphocyte response and increased splenic CD11b (+) Gr-1 (+) myeloid-derived suppressor cells require HMGB1. Mediators Inflamm 2015:458626, 2015.
Szott LM, Horbett TA. The role of complement C3 and fibrinogen in monocyte adhesion to PEO-like plasma deposited tetraglyme. J Biomed Mater Res A 95 (4):1252–1260, 2010.
McNally AK, Anderson JM. Complement C3 participation in monocyte adhesion to different surfaces. Proc Natl Acad Sci U S A 91 (21):10119–10123, 1994.
Zhang C, Wang C, Li Y, Miwa T, Liu C, Cui W, Song WC, Du J. Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking. Nat Commun 8 (1):2078, 2017.
Gavin C, Meinke S, Heldring N, Heck KA, Achour A, Iacobaeus E, Hoglund P, Le Blanc K, Kadri N. The complement system is essential for the phagocytosis of mesenchymal stromal cells by monocytes. Front Immunol 10:2249, 2019.
Brekke OL, Christiansen D, Fure H, Fung M, Mollnes TE. The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood. J Leukoc Biol 81 (6):1404–1413, 2007.
Lausen M, Christiansen G, Karred N, Winther R, Poulsen TBG, Palarasah Y, Birkelund S. Complement C3 opsonization of Chlamydia trachomatis facilitates uptake in human monocytes. Microbes Infect 20 (6):328–336, 2018.
Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Kohl J, Cook HT, Kemper C. C3a modulates IL-1beta secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122 (20):3473–3481, 2013.
Killick J, Morisse G, Sieger D, Astier AL. Complement as a regulator of adaptive immunity. Semin Immunopathol 40 (1):37–48, 2018.
Marin AV, Cardenas PP, Jimenez-Reinoso A, Munoz-Ruiz M, Regueiro JR. Lymphocyte integration of complement cues. Semin Cell Dev Biol 85:132–142, 2019.
Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG, Fara AF, Subias M, Pickering MC, Drouet C, Meri S, et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39 (6):1143–1157, 2013.
Szabo PA, Levitin HM, Miron M, Snyder ME, Senda T, Yuan J, Cheng YL, Bush EC, Dogra P, Thapa P, et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat Commun 10 (1):4706, 2019.
Guillaumet-Adkins A, Rodriguez-Esteban G, Mereu E, Mendez-Lago M, Jaitin DA, Villanueva A, Vidal A, Martinez-Marti A, Felip E, Vivancos A, et al. Single-cell transcriptome conservation in cryopreserved cells and tissues. Genome Biol 18 (1):45, 2017.