Phagocytosis is a complex process by which cells within most organ systems remove pathogens and cell debris. Phagocytosis is usually followed by inflammatory pathway activation, which promotes pathogen elimination and inhibits pathogen growth. Delayed pathogen elimination is the first step in sepsis development and a key factor in sepsis resolution. Phagocytosis thus has an important role during sepsis and likely contributes to all of its clinical stages. However, only a few studies have specifically explored and characterized phagocytic activity during sepsis. Here, we describe the phagocytic processes that occur as part of the immune response preceding sepsis onset and identify the elements of phagocytosis that might constitute a predictive marker of sepsis outcomes. First, we detail the key features of phagocytosis, including the main receptors and signaling hallmarks associated with different phagocytic processes. We then discuss how the initial events of phagosome formation and cytoskeletal remodeling might be associated with known sepsis features, such as a cytokine-driven hyperinflammatory response and immunosuppression. Finally, we highlight the unresolved mechanisms of sepsis development and progression and the need for cross-disciplinary approaches to link the clinical complexity of the disease with basic cellular and molecular mechanisms.

Department of Anesthesiology and Intensive Care Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Zobrazit více v PubMed

Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 395:200–211, 2020. PubMed PMC

Yadav H, Cartin-Ceba R. Balance between hyperinflammation and immunosuppression in sepsis. Semin Respir Crit Care Med 37:42–50, 2016. PubMed

Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 13:260–268, 2013. PubMed PMC

Cao C, Yu M, Chai Y. Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell Death Dis 10:782, 2019. PubMed PMC

Cohen J, Vincent JL, Adhikari NKJ, Machado FR, Angus DC, Calandra T, Jaton K, Giulieri S, Delaloye J, Opal S, et al. Sepsis: a roadmap for future research. Lancet Infect Dis 15:581–614, 2015. PubMed

De La Rica AS, Gilsanz F, Maseda E. Epidemiologic trends of sepsis in western countries. Ann Transl Med 4:325, 2016. PubMed PMC

Underhill DM, Ozinsky A. Phagocytosis of microbes: complexity in action. Annu Rev Immunol 20:825–852, 2002. PubMed

Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr Opin Immunol 14:136–145, 2002. PubMed

Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev 262:193–215, 2014. PubMed

Salvi AM, DeMali KA. Mechanisms linking mechanotransduction and cell metabolism. Curr Opin Cell Biol 54:114–120, 2018. PubMed PMC

Gordon S. Phagocytosis: an immunobiologic process. Immunity 44:463–475, 2016. PubMed

Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17:593–623, 1999. PubMed

Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 16:343–353, 2015. PubMed PMC

Okayama Y, Kirshenbaum AS, Metcalfe DD. Expression of a functional high-affinity IgG receptor, FcγRI, on human mast cells: up-regulation by IFN-γ. J Immunol 164:4332–4339, 2000. PubMed

Arredouani MS, Palecanda A, Koziel H, Huang Y-C, Imrich A, Sulahian TH, Ning YY, Yang Z, Pikkarainen T, Sankala M, et al. MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages. J Immunol 175:6058–6064, 2005. PubMed

Killpack TL, Ballesteros M, Bunnell SC, Bedugnis A, Kobzik L, Hu LT, Petnicki-Ocwieja T. Phagocytic receptors activate Syk and Src signaling during Borrelia burgdorferi phagocytosis. Infect Immun 85:1–11, 2017. PubMed PMC

Fadok VA, Warner ML, Bratton DL, Henson PM. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). J Immunol 161:6250–6257, 1998. PubMed

Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R, Hazen SL. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med 203:2613–2625, 2006. PubMed PMC

Freeman SA, Goyette J, Furuya W, Woods EC, Bertozzi CR, Bergmeier W, Hinz B, van der Merwe PA, Das R, Grinstein S. Integrins form an expanding diffusional barrier that coordinates phagocytosis. Cell 164:128–140, 2016. PubMed PMC

Fric J, Zelante T, Ricciardi-Castagnoli P. Phagocytosis of particulate antigens—all roads lead to calcineurin/NFAT signaling pathway. Front Immunol 4:513, 2014. PubMed PMC

Underhill DM, Gantner B. Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect 6:1368–1373, 2004. PubMed

Da Silva FP, Aloulou M, Skurnik D, Benhamou M, Andremont A, Velasco IT, Chiamolera M, Verbeek JS, Launay P, Monteiro RC. CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nat Med 13:1368–1374, 2007. PubMed

Van Avondt K, van Sorge NM, Meyaard L. Bacterial immune evasion through manipulation of host inhibitory immune signaling. PLoS Pathog 11:e1004644, 2015. PubMed PMC

Beppler J, Mkaddem Ben, Michaloski J, Honorato RV, Velasco IT, de Oliveira PSL, Giordano RJ, Monteiro RC, Pinheiro da Silva F. Negative regulation of bacterial killing and inflammation by two novel CD16 ligands. Eur J Immunol 46:1926–1935, 2016. PubMed

Baker CC, Chaudry IH, Gaines HO, Baue AE. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery 94:331–335, 1983. PubMed

Liu JR, Han X, Soriano SG, Yuki K. The role of macrophage 1 antigen in polymicrobial sepsis. Shock 42:532–539, 2014. PubMed

Jawhara S, Pluskota E, Cao W, Plow EF, Soloviev DA. Distinct effects of integrins αXβ2 and αMβ2 on leukocyte subpopulations during inflammation and antimicrobial responses. Infect Immun 85:1–17, 2017. PubMed PMC

Wolf D, Anto-Michel N, Blankenbach H, Wiedemann A, Buscher K, Hohmann JD, Lim B, Bäuml M, Marki A, Mauler M, et al. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nat Commun 9:525, 2018. PubMed PMC

Leelahavanichkul A, Bocharov AV, Kurlander R, Baranova IN, Vishnyakova TG, Souza ACP, Hu X, Doi K, Vaisman B, Amar M, et al. Class B scavenger receptor types I and II and CD36 targeting improves sepsis survival and acute outcomes in mice. J Immunol 188 (6):2749–2758, 2012. PubMed PMC

Guo C, Yi H, Yu X, Hu F, Zuo D, Subjeck JR, Wang XY. Absence of scavenger receptor A promotes dendritic cell-mediated cross-presentation of cell-associated antigen and antitumor immune response. Immunol Cell Biol 90:101–108, 2012. PubMed PMC

de Tymowski C, Heming N, Correia MDT, Abbad L, Chavarot N, Le Stang MB, Flament H, Bex J, Boedec E, Bounaix C, et al. CD89 is a potent innate receptor for bacteria and mediates host protection from sepsis. Cell Rep 27:762.e5–775.e5, 2019. PubMed

Davies LC, Rice CM, McVicar DW, Weiss JM. Diversity and environmental adaptation of phagocytic cell metabolism. J Leukoc Biol 105:37–48, 2019. PubMed PMC

Rimmelé T, Payen D, Cantaluppi V, Marshall J, Gomez H, Gomez A, Murray P, Kellum JA. Immune cell phenotype and function in sepsis. Shock 45:282–291, 2016. PubMed PMC

Cavaillon J-M, Adrie C, Fitting C, Adib-Conquy M. Reprogramming of circulatory cells in sepsis and SIRS. J Endotoxin Res 11:311–320, 2005. PubMed

Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 56:672–686, 1994. PubMed

Stiel L, Meziani F, Helms J. Neutrophil activation during septic shock. Shock 49:371–384, 2018. PubMed

Benjamim CF, Silva JS, Fortes ZB, Oliveira MA, Ferreira SH, Cunha FQ. Inhibition of leukocyte rolling by nitric oxide during sepsis leads to reduced migration of active microbicidal neutrophils. Infect Immun 70:3602–3610, 2002. PubMed PMC

Skoutelis AT, Kaleridis V, Athanassiou GM, Kokkinis KI, Missirlis YF, Bassaris HP. Neutrophil deformability in patients with sepsis, septic shock, and adult respiratory distress syndrome. Crit Care Med 28:2355–2359, 2000. PubMed

Lindbom L, Xie X, Raud J, Hedqvist P. Chemoattractant-induced firm adhesion of leukocytes to vascular endothelium in vivo is critically dependent on initial leukocyte rolling. Acta Physiol Scand 146:415–421, 1992. PubMed

Danikas DD, Karakantza M, Theodorou GL, Sakellaropoulos GC, Gogos CA. Prognostic value of phagocytic activity of neutrophils and monocytes in sepsis. Correlation to CD64 and CD14 antigen expression. Clin Exp Immunol 154:87–97, 2008. PubMed PMC

Taneja R, Sharma AP, Hallett MB, Findlay GP, Morris MR. Immature circulating neutrophils in sepsis have impaired phagocytosis and calcium signaling. Shock 30:618–622, 2008. PubMed

Ziegler-Heitbrock L. Blood monocytes and their subsets: established features and open questions. Front Immunol 6:423, 2015. PubMed PMC

Fingerle G, Pforte A, Passlick B, Blumenstein M, Strobel M, Ziegler-Heitbrock HWL. The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood 82:3170–3176, 1993. PubMed

Mukherjee R, Kanti Barman P, Kumar Thatoi P, Tripathy R, Kumar Das B, Ravindran B. Non-Classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous. Sci Rep 5:13886, 2015. PubMed PMC

Döring M, Cabanillas Stanchi KM, Erbacher A, Haufe S, Schwarze CP, Handgretinger R, Hofbeck M, Kerst G. Phagocytic activity of monocytes, their subpopulations and granulocytes during post-transplant adverse events after hematopoietic stem cell transplantation. Immunobiology 220:605–613, 2015. PubMed

Gainaru G, Papadopoulos A, Tsangaris I, Lada M, Giamarellos-Bourboulis EJ, Pistiki A. Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: Correlation with final outcome. Crit Care 22:56, 2018. PubMed PMC

Chung H, Lee JH, Jo YH, Hwang JE, Kim J. Circulating monocyte counts and its impact on outcomes in patients with severe sepsis including septic shock. SHOCK 51:423–429, 2019. PubMed

Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33:375–386, 2010. PubMed PMC

Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2:1, 2014. PubMed PMC

Ferreira da Mota NV, Brunialti MKC, Santos SS, Machado FR, Assuncao M, Azevedo LCP, Salomao R. Immunophenotyping of monocytes during human sepsis shows impairment in antigen presentation. Shock 50:293–300, 2018. PubMed

Xu P, Lou J-S, Ren Y, Miao C, Deng X. Gene expression profiling reveals the defining features of monocytes from septic patients with compensatory anti-inflammatory response syndrome. J Infect 65:380–391, 2012. PubMed

Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30:475–487, 2009. PubMed

Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447:972–978, 2007. PubMed

Grondman I, Arts RJW, Koch RM, Leijte GP, Gerretsen J, Bruse N, Kempkes RWM, Ter Horst R, Kox M, Pickkers P, et al. Frontline science: endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst. J Leukoc Biol 106:11–25, 2019. PubMed PMC

Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, DI Conza G, Cheng WC, Chou CH, Vavakova M, et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol 18:985–994, 2017. PubMed

Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 335:936–941, 2012. PubMed PMC

Pena OM, Pistolic J, Raj D, Fjell CD, Hancock REW. Endotoxin tolerance represents a distinctive state of alternative polarization (m2) in human mononuclear cells. J Immunol 186:7243–7254, 2011. PubMed

Avendaño-Ortiz J, Maroun-Eid C, Martín-Quirós A, Toledano V, Cubillos-Zapata C, Gómez-Campelo P, Varela-Serrano A, Casas-Martin J, Llanos-González E, Alvarez E, et al. PD-L1 overexpression during endotoxin tolerance impairs the adaptive immune response in septic patients via HIF1α. J Infect Dis 217:393–404, 2018. PubMed

del Fresno C, García-Rio F, Gómez-Piña V, Soares-Schanoski A, Fernández-Ruíz I, Jurado T, Kajiji T, Shu C, Marín E, Gutierrez del Arroyo A, et al. Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J Immunol 182:6494–6507, 2009. PubMed

Mehta A, Brewington R, Chatterji M, Zoubine M, Kinasewitz GT, Peer GT, Chang ACK, Taylor FB, Shnyra A. Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis. Shock 22:423–430, 2004. PubMed

Wiersinga WJ, Veer CVT, Van Den Pangaart PS, Dondorp AM, Day NP, Peacock SJ, Van Der Poll T. Immunosuppression associated with interleukin-1R-associated-kinase-M upregulation predicts mortality in gram-negative sepsis (melioidosis). Crit Care Med 37:569–576, 2009. PubMed

Escoll P, del Fresno C, García L, Vallés G, Lendínez MJ, Arnalich F, López-Collazo E. Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients. Biochem Biophys Res Commun 311:465–472, 2003. PubMed

Santos SS, Carmo AM, Brunialti MKC, Machado FR, Azevedo LC, Assunção M, Trevelin SC, Cunha FQ, Salomao R. Modulation of monocytes in septic patients: preserved phagocytic activity, increased ROS and NO generation, and decreased production of inflammatory cytokines. Intensive Care Med Exp 4:5, 2016. PubMed PMC

Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos CA. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Vaccine Immunol 11:161–167, 2004. PubMed PMC

Patera AC, Drewry AM, Chang K, Beiter ER, Osborne D, Hotchkiss RS. Frontline Science: defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1. J Leukoc Biol 100:1239–1254, 2016. PubMed PMC

Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, Nürnberg P, Schultz MJ, Horn J, Cremer OL, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 5:816–826, 2017. PubMed

Pechkovsky DV, Potapnev MP, Zalutskaya OM. Different patterns of cytokine regulation of phagocytosis and bacterial killing by human neutrophils. Int J Antimicrob Agents 7:33–40, 1996. PubMed

Henan X, Toyota N, Yanjiang X, Fujita Y, Zhijun H, Touma M, Qiong W, Sugimoto K. Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation. BMB Rep 47:286–291, 2014. PubMed PMC

Monneret G, Finck M-E, Venet F, Debard A-L, Bohé J, Bienvenu J, Lepape A. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett 95:193–198, 2004. PubMed

Leemans JC, Juffermans NP, Florquin S, van Rooijen N, Vervoordeldonk MJ, Verbon A, van Deventer SJH, van der Poll T. Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. J Immunol 166:4604–4611, 2001. PubMed

Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765, 2001. PubMed

Honore PM, Hoste E, Molnár Z, Jacobs R, Joannes-Boyau O, Malbrain MLNG, Forni LG. Cytokine removal in human septic shock: where are we and where are we going? Ann Intensive Care 9:56, 2019. PubMed PMC

Broman ME, Hansson F, Vincent JL, Bodelsson M. Endotoxin and cytokine reducing properties of the oXiris membrane in patients with septic shock: a randomized crossover double-blind study. PLoS One 14:e0220444, 2019. PubMed PMC

Monard C, Rimmelé T, Ronco C. Extracorporeal blood purification therapies for sepsis. Blood Purif 47:2–15, 2019. PubMed

Mathias B, Szpila BE, Moore FA, Efron PA, Moldawer LL. A review of GM-CSF therapy in sepsis. Medicine (Baltimore) 94:e2044, 2015. PubMed PMC

Chousterman BG, Arnaud M. Is there a role for hematopoietic growth factors during sepsis? Front Immunol 9:1015, 2018. PubMed PMC

Spath S, Komuczki J, Hermann M, Pelczar P, Mair F, Schreiner B, Becher B. Dysregulation of the cytokine GM-CSF induces spontaneous phagocyte invasion and immunopathology in the central nervous system. Immunity 46:245–260, 2017. PubMed

Pierce A, Pittet JF. Inflammatory response to trauma: Implications for coagulation and resuscitation. Curr Opin Anaesthesiol 27:246–252, 2014. PubMed PMC

Flores-Mejía LA, Cabrera-Rivera GL, Ferat-Osorio E, Mancilla-Herrera I, Torres-Rosas R, Boscó-Garate IB, López-Macías C, Isibasi A, Cérbulo-Vazquez A, Arriaga-Pizano LA. Function is dissociated from activation-related immunophenotype on phagocytes from patients with SIRS/Sepsis Syndrome. Shock 52:E68–E75, 2019. PubMed

Papathanassoglou EDE, Moynihan JA, Ackerman MH. Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? A review and a theoretical framework. Crit Care Med 28:537–549, 2000. PubMed

Cui YL, Qiu LH, Zhou SY, Li LF, Qian ZZ, Liu XM, Zhang HL, Ren XB, Wang YQ. Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome. Oncotarget 8:56980–56990, 2017. PubMed PMC

Freise N, Burghard A, Ortkras T, Daber N, Chasan AI, Jauch SL, Fehler O, Hillebrand J, Schakaki M, Rojas J, et al. Signaling mechanisms inducing hyporesponsiveness of phagocytes during systemic inflammation. Blood 134:134–146, 2019. PubMed

Clark JA, Coopersmith CM. Intestinal crosstalk: a new paradigm for understanding the gut as the “motor” of critical illness. Shock 28:384–393, 2007. PubMed PMC

Otani S, Coopersmith CM. Gut integrity in critical illness. J Intensive Care 7:17, 2019. PubMed PMC

Cheng S-C, Scicluna BP, Arts RJW, Gresnigt MS, Lachmandas E, Giamarellos-Bourboulis EJ, Kox M, Manjeri GR, Wagenaars JAL, Cremer OL, et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 17:406–413, 2016. PubMed

Dreschers S, Ohl K, Lehrke M, Möllmann J, Denecke B, Costa I, Vogl T, Viemann D, Roth J, Orlikowsky T, et al. Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats. Nat Commun 10:1685, 2019. PubMed PMC

Hamers L, Kox M, Pickkers P. Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiol 81:426–439, 2015. PubMed

Amatullah H, Shan Y, Beauchamp BL, Gali PL, Gupta S, Maron-Gutierrez T, Speck ER, Fox-Robichaud AE, Tsang JLY, Mei SHJ, et al. DJ-1/PARK7 Impairs bacterial clearance in sepsis. Am J Respir Crit Care Med 195:889–905, 2017. PubMed

Gu J, Luo L, Wang Q, Yan S, Lin J, Li D, Cao B, Mei H, Ying B, Bin L, et al. Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients. Lab Investig 98:715–733, 2018. PubMed

Victor V, Esplugues J, Hernandez-Mijares A, Rocha M. Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondria-targeted antioxidants. Infect Disord Drug Targets 9:376–389, 2012. PubMed

Lewis AJ, Billiar TR, Rosengart MR. Biology and metabolism of sepsis: innate immunity, bioenergetics, and autophagy. Surg Infect (Larchmt) 17:286–293, 2016. PubMed PMC

Venter G, Oerlemans FTJJ, Wijers M, Willemse M, Fransen JAM, Wieringa B. Glucose controls morphodynamics of LPS-stimulated macrophages. PLoS One 9:e96786, 2014. PubMed PMC

Wong SY, Guerdoud LM, Cantin A, Speert DP. Glucose stimulates phagocytosis of unopsonized Pseudomonas aeruginosa by cultivated human alveolar macrophages. Infect Immun 67:16–21, 1999. PubMed PMC

Galván-Peña S, O’Neill LAJ. Metabolic reprograming in macrophage polarization. Front Immunol 5:420, 2014. PubMed PMC

Canton J, Khezri R, Glogauer M, Grinstein S. Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages. Mol Biol Cell 25:3330–3341, 2014. PubMed PMC

Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. Int J Biol Sci 10:520–529, 2014. PubMed PMC

Nascimento DC, Melo PH, Piñeros AR, Ferreira RG, Colón DF, Donate PB, Castanheira FV, Gozzi A, Czaikoski PG, Niedbala W, et al. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population. Nat Commun 8:1–14, 2017. PubMed PMC

Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature 509:310–317, 2014. PubMed PMC

Zumerle S, Calì B, Munari F, Angioni R, Di Virgilio F, Molon B, Viola A. Intercellular calcium signaling induced by ATP potentiates macrophage phagocytosis. Cell Rep 27:1.e4–10.e4, 2019. PubMed PMC

Wischmeyer PE. Nutrition Therapy in Sepsis. Crit Care Clin 34:107–125, 2018. PubMed PMC

Prescott HC, Chang VW, O’Brien JM, Langa KM, Iwashyna TJ. Obesity and 1-year outcomes in older Americans with severe sepsis. Crit Care Med 42:1766–1774, 2014. PubMed PMC

Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 15:335–349, 2015. PubMed PMC

Kiers HD, Scheffer G-J, van der Hoeven JG, Eltzschig HK, Pickkers P, Kox M. Immunologic consequences of hypoxia during critical illness. Anesthesiology 125:237–249, 2016. PubMed PMC

Walrand S, Guillet C, Boirie Y, Vasson M-P. In vivo evidences that insulin regulates human polymorphonuclear neutrophil functions. J Leukoc Biol 76:1104–1110, 2004. PubMed

Wang N, Gates KL, Trejo H, Favoreto S, Schleimer RP, Sznajder JI, Beitel GJ, Sporn PHS. Elevated CO 2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. FASEB J 24:2178–2190, 2010. PubMed PMC

Patel VS, Sampat V, Espey MG, Sitapara R, Wang H, Yang X, Ashby CR, Thomas DD, Mantell LL. Ascorbic acid attenuates hyperoxia-compromised host defense against pulmonary bacterial infection. Am J Respir Cell Mol Biol 55:511–520, 2016. PubMed PMC

Jaffal K, Six S, Zerimech F, Nseir S. Relationship between hyperoxemia and ventilator associated pneumonia. Ann Transl Med 5:453, 2017. PubMed PMC

Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, Holmes M, Reynolds PN. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 178:139–148, 2008. PubMed

Emmet O’Brien M, Restrepo MI, Martin-Loeches I. Update on the combination effect of macrolide antibiotics in community-acquired pneumonia. Respir Investig 53:201–209, 2015. PubMed

Labro MT. Interference of antibacterial agents with phagocyte functions: Immunomodulation or “Immuno-Fairy Tales”? Clin Microbiol Rev 13:615–650, 2000. PubMed PMC

Yang JH, Bhargava P, McCloskey D, Mao N, Palsson BO, Collins JJ. Antibiotic-induced changes to the host metabolic environment inhibit drug efficacy and alter immune function. Cell Host Microbe 22:757.e3–765.e3, 2017. PubMed PMC

Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA. Induction of M2 regulatory macrophages through the β2-adrenergic receptor with protection during endotoxemia and acute lung injury. J Innate Immun 6:607–618, 2014. PubMed PMC

Zhou J, Yan J, Liang H, Jiang J. Epinephrine enhances the response of macrophages under LPS stimulation. Biomed Res Int 2014:1–8, 2014. PubMed PMC

Wiedermann FJ, Watzinger K, Stichlberger M, Joannidis M, Kaehler C, Lederer W. Effects of arginine vasopressin on migration and respiratory burst activity in human leukocytes. Open Med (Wars) 13:122–129, 2018. PubMed PMC

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377, 2017. PubMed

Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating sepsis. Cochrane Database Syst Rev 2015:CD002243, 2015. PubMed PMC

Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk H-D, Doecke W-D, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock. Am J Respir Crit Care Med 167:512–520, 2003. PubMed

Brown GD, Herre J, Williams DL, Willment JA, Marshall ASJ, Gordon S. Dectin-1 mediates the biological effects of β-Glucans. J Exp Med 197:1119–1124, 2003. PubMed PMC

Herre J, Marshall ASJ, Caron E, Edwards AD, Williams DL, Schweighoffer E, Tybulewicz V, Reis e Sousa C, Gordon S, Brown GD. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood 104:4038–4045, 2004. PubMed

Platt N, Suzuki H, Kurihara Y, Kodama T, Gordon S. Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc Natl Acad Sci 93:12456–12460, 1996. PubMed PMC

Amiel E, Alonso A, Uematsu S, Akira S, Poynter ME, Berwin B. Pivotal Advance: toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis. J Leukoc Biol 85:595–605, 2009. PubMed PMC

Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188:2313–2320, 1998. PubMed PMC

Le Cabec V, Carréno S, Moisand A, Bordier C, Maridonneau-Parini I. Complement receptor 3 (CD11b/CD18) mediates type i and type ii phagocytosis during nonopsonic and opsonic phagocytosis, respectively. J Immunol 169:2003–2009, 2002. PubMed

García-García E, Rosales C. Signal transduction during Fc receptor-mediated phagocytosis. J Leukoc Biol 72:1092–1108, 2002. PubMed

Tohyama Y, Yamamura H. Protein tyrosine kinase, syk: a key player in phagocytic cells. J Biochem 145:267–273, 2009. PubMed

Goodridge HS, Underhill DM, Touret N. Mechanisms of Fc receptor and Dectin-1 activation for phagocytosis. Traffic 13:1062–1071, 2012. PubMed

Lukácsi S, Nagy-Baló Z, Erdei A, Sándor N, Bajtay Z. The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes. Immunol Lett 189:64–72, 2017. PubMed

Dupuy AG, Caron E. Integrin-dependent phagocytosis—spreading from microadhesion to new concepts. J Cell Sci 121:1773–1783, 2008. PubMed

Prognostic value of soluble endoglin in patients with septic shock and severe COVID-19

Lung Organoids-The Ultimate Tool to Dissect Pulmonary Diseases?

Differences in monocyte subsets are associated with short-term survival in patients with septic shock