RESUMEN
Macrophages and conventional dendritic cells (cDCs) are distributed throughout the body, maintaining tissue homeostasis and tolerance to self and orchestrating innate and adaptive immunity against infection and cancer. As they complement each other, it is important to understand how they cooperate and the mechanisms that integrate their functions. Both are exposed to commensal microbes, pathogens, and other environmental challenges that differ widely among anatomical locations and over time. To adjust to these varying conditions, macrophages and cDCs acquire spatiotemporal adaptations (STAs) at different stages of their life cycle that determine how they respond to infection. The STAs acquired in response to previous infections can result in increased responsiveness to infection, termed training, or in reduced responses, termed paralysis, which in extreme cases can cause immunosuppression. Understanding the developmental stage and location where macrophages and cDCs acquire their STAs, and the molecular and cellular players involved in their induction, may afford opportunities to harness their beneficial outcomes and avoid or reverse their deleterious effects. Here we review our current understanding of macrophage and cDC development, life cycle, function, and STA acquisition before, during, and after infection.We propose a unified framework to explain how these two cell types adjust their activities to changing conditions over space and time to coordinate their immunosurveillance functions.
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Inmunidad Adaptativa , Células Dendríticas , Animales , Diferenciación Celular , Humanos , Tolerancia Inmunológica , MacrófagosRESUMEN
The growth of antimicrobial resistance (AMR) highlights an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe infections profoundly alter host metabolism, prior studies have largely ignored microbial metabolism in this context. Here, we describe an iterative, comparative metabolomics pipeline to uncover microbial metabolic features in the complex setting of a host and apply it to investigate gram-negative bloodstream infection (BSI) in patients. We find elevated levels of bacterially derived acetylated polyamines during BSI and discover the enzyme responsible for their production (SpeG). Blocking SpeG activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity also enhances bacterial membrane permeability and increases intracellular antibiotic accumulation, allowing us to overcome AMR in culture and in vivo. This study highlights how tools to study pathogen metabolism in the natural context of infection can reveal and prioritize therapeutic strategies for addressing challenging infections.
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Metabolómica , Poliaminas , Humanos , Animales , Poliaminas/metabolismo , Ratones , Bacteriemia/microbiología , Bacteriemia/metabolismo , Bacteriemia/tratamiento farmacológico , Antibacterianos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/metabolismo , FemeninoRESUMEN
The introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the human population represents a tremendous medical and economic crisis. Innate immunity-as the first line of defense of our immune system-plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for coronavirus disease 2019 (COVID-19), the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which so far are lagging behind.
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COVID-19/inmunología , Interacciones Microbiota-Huesped , Inmunidad Innata , SARS-CoV-2/fisiología , Humanos , Índice de Severidad de la EnfermedadRESUMEN
Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone with poorly defined biology. Here, we investigated the role of GDF15 in bacterial and viral infections. We found that inflammation induced GDF15, and that GDF15 was necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance. Indeed, we found that GDF15 was required for hepatic sympathetic outflow and triglyceride metabolism. Failure to defend the lower limit of plasma triglyceride levels was associated with impaired cardiac function and maintenance of body temperature, effects that could be rescued by exogenous administration of lipids. Together, we show that GDF15 coordinates tolerance to inflammatory damage through regulation of triglyceride metabolism.
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Factor 15 de Diferenciación de Crecimiento/metabolismo , Hígado/metabolismo , Sepsis/patología , Animales , Anticuerpos/farmacología , Modelos Animales de Enfermedad , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/inmunología , Corazón/efectos de los fármacos , Corazón/virología , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Orthomyxoviridae/patogenicidad , Poli I-C/toxicidad , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , Sepsis/sangre , Sepsis/mortalidad , Tasa de Supervivencia , Triglicéridos/sangre , Triglicéridos/metabolismo , Troponina I/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.
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Dipeptidasas/metabolismo , Neutrófilos/fisiología , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Animales , Cilastatina/farmacología , Cilastatina/uso terapéutico , Dipeptidasas/antagonistas & inhibidores , Dipeptidasas/genética , Modelos Animales de Enfermedad , Endotoxemia/mortalidad , Endotoxemia/patología , Endotoxemia/prevención & control , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Infiltración Neutrófila/efectos de los fármacos , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Tasa de SupervivenciaRESUMEN
Sepsis is a dysregulated inflammatory consequence of systemic infection. As a result, excessive platelet activation leads to thrombosis and coagulopathy, but we currently lack sufficient understanding of these processes. Here, using the cecal ligation and puncture (CLP) model of sepsis, we observed septic thrombosis and neutrophil extracellular trap formation (NETosis) within the mouse vasculature by intravital microscopy. STING activation in platelets was a critical driver of sepsis-induced pathology. Platelet-specific STING deficiency suppressed platelet activation and granule secretion, which alleviated sepsis-induced intravascular thrombosis and NETosis in mice. Mechanistically, sepsis-derived cGAMP promoted the binding of STING to STXBP2, the assembly of SNARE complex, granule secretion, and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. We generated a peptide, C-ST5, to block STING binding to STXBP2. Septic mice treated with C-ST5 showed reduced thrombosis. Overall, platelet activation via STING reveals a potential strategy for limiting life-threatening sepsis-mediated coagulopathy.
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Trampas Extracelulares , Sepsis , Trombosis , Animales , Ratones , Plaquetas/metabolismo , Trampas Extracelulares/metabolismo , Ratones Endogámicos C57BL , Proteínas Munc18/metabolismo , Activación Plaquetaria , Sepsis/metabolismo , Trombosis/metabolismoRESUMEN
The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae (P. merdae) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P. merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.
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Microbioma Gastrointestinal , Sepsis , Embarazo , Femenino , Humanos , Animales , Ratones , Microbioma Gastrointestinal/fisiología , Piroptosis/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Macrófagos/metabolismo , Sepsis/metabolismo , Inflamación/metabolismoRESUMEN
Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.
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Proteína Antagonista del Receptor de Interleucina 1 , Sepsis , Humanos , Candida albicans , Macrófagos , Receptores de Interleucina-1RESUMEN
Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
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Glucosa/metabolismo , Hierro/metabolismo , Sepsis/metabolismo , Animales , Apoferritinas/genética , Apoferritinas/metabolismo , Ceruloplasmina/metabolismo , Gluconeogénesis , Glucosa-6-Fosfatasa/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Blood platelets are critical for hemostasis and thrombosis and play diverse roles during immune responses. Despite these versatile tasks in mammalian biology, their skills on a cellular level are deemed limited, mainly consisting in rolling, adhesion, and aggregate formation. Here, we identify an unappreciated asset of platelets and show that adherent platelets use adhesion receptors to mechanically probe the adhesive substrate in their local microenvironment. When actomyosin-dependent traction forces overcome substrate resistance, platelets migrate and pile up the adhesive substrate together with any bound particulate material. They use this ability to act as cellular scavengers, scanning the vascular surface for potential invaders and collecting deposited bacteria. Microbe collection by migrating platelets boosts the activity of professional phagocytes, exacerbating inflammatory tissue injury in sepsis. This assigns platelets a central role in innate immune responses and identifies them as potential targets to dampen inflammatory tissue damage in clinical scenarios of severe systemic infection.
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Infecciones Bacterianas/inmunología , Plaquetas/inmunología , Animales , Bacterias/clasificación , Plaquetas/citología , Vasos Sanguíneos/lesiones , Vasos Sanguíneos/patología , Calcio/metabolismo , Movimiento Celular , Polaridad Celular , Humanos , Inflamación/inmunología , Integrinas/metabolismo , Ratones , Miosinas/metabolismo , Neutrófilos/citologíaRESUMEN
During gram-negative septicemia, interactions between platelets and neutrophils initiate a detrimental feedback loop that sustains neutrophil extracellular trap (NET) induction, disseminated intravascular coagulation, and inflammation. Understanding intracellular pathways that control platelet-neutrophil interactions is essential for identifying new therapeutic targets. Here, we found that thrombin signaling induced activation of the transcription factor NFAT in platelets. Using genetic and pharmacologic approaches, as well as iNFATuation, a newly developed mouse model in which NFAT activation can be abrogated in a cell-specific manner, we demonstrated that NFAT inhibition in activated murine and human platelets enhanced their activation and aggregation, as well as their interactions with neutrophils and NET induction. During gram-negative septicemia, NFAT inhibition in platelets promoted disease severity by increasing disseminated coagulation and NETosis. NFAT inhibition also partially restored coagulation ex vivo in patients with hypoactive platelets. Our results define non-transcriptional roles for NFAT that could be harnessed to address pressing clinical needs.
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Plaquetas/efectos de los fármacos , Factores de Transcripción NFATC/antagonistas & inhibidores , Agregación Plaquetaria/efectos de los fármacos , Sepsis/patología , Animales , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/metabolismo , Comunicación Celular/efectos de los fármacos , Gránulos Citoplasmáticos/metabolismo , Modelos Animales de Enfermedad , Trampas Extracelulares/metabolismo , Humanos , Inflamación , Ratones , Factores de Transcripción NFATC/metabolismo , Neutrófilos/metabolismo , Receptores de Trombina/metabolismo , Sepsis/metabolismoRESUMEN
The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.
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COVID-19 , Sepsis , Animales , Ratones , Actinas , Cromatina , Desoxirribonucleasa I , ADN , Neutrófilos , ProteómicaRESUMEN
Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.
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Factor Estimulante de Colonias de Macrófagos , Células Madre Mesenquimatosas , Animales , Médula Ósea , Células de la Médula Ósea , Células Endoteliales , Factor Estimulante de Colonias de Macrófagos/farmacología , Ratones , MonocitosRESUMEN
The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.
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Apolipoproteína L1/genética , Población Negra/genética , COVID-19/genética , Predisposición Genética a la Enfermedad/genética , Sepsis/genética , Animales , Apolipoproteína L1/sangre , Población Negra/estadística & datos numéricos , COVID-19/patología , ADN Mitocondrial/metabolismo , Células Endoteliales/metabolismo , Humanos , Inflamación/genética , Inflamación/patología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Mitofagia/genética , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factores de Riesgo , Sepsis/patología , Índice de Severidad de la Enfermedad , Población Blanca/genética , Población Blanca/estadística & datos numéricosRESUMEN
Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.
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Anticoagulantes/uso terapéutico , Caspasas/metabolismo , Heparina/uso terapéutico , Macrófagos/inmunología , Sepsis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Caspasas/genética , Línea Celular , Femenino , Glucuronidasa/genética , Glucuronidasa/metabolismo , Glicocálix/metabolismo , Proteína HMGB1/metabolismo , Humanos , Inmunomodulación , Lipopolisacáridos/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Sepsis/mortalidad , Análisis de Supervivencia , Adulto JovenRESUMEN
Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omentum revealed that large peritoneal macrophages (LPMs) rapidly cleared bacteria and adhered to the mesothelium, forming multilayered cellular aggregates composed by sequentially recruited LPMs, B1 cells, neutrophils, and monocyte-derived cells (moCs). The formation of resident macrophage aggregates (resMφ-aggregates) required LPMs and thrombin-dependent fibrin polymerization. E. coli infection triggered LPM pyroptosis and release of inflammatory mediators. Resolution of these potentially inflammatory aggregates required LPM-mediated recruitment of moCs, which were essential for fibrinolysis-mediated resMφ-aggregate disaggregation and the prevention of peritoneal overt inflammation. Thus, resMφ-aggregates provide a physical scaffold that enables the efficient control of peritoneal infection, with implications for antimicrobial immunity in other body cavities, such as the pleural cavity or brain ventricles.
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Infecciones Bacterianas/etiología , Infecciones Bacterianas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Cavidad Peritoneal/microbiología , Animales , Biomarcadores , Microambiente Celular/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Mediadores de Inflamación/metabolismo , Ratones , Peritonitis/etiología , Peritonitis/metabolismo , Peritonitis/patologíaRESUMEN
Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.
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Adenosina/inmunología , Antígenos CD/inmunología , Apirasa/inmunología , Tolerancia Inmunológica/inmunología , Macrófagos/inmunología , Células Plasmáticas/inmunología , Sepsis/inmunología , Adenosina/metabolismo , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Reprogramación Celular/inmunología , Macrófagos/metabolismo , Ratones , Células Plasmáticas/metabolismo , Receptor de Adenosina A2A/inmunología , Receptor de Adenosina A2A/metabolismo , Sepsis/metabolismoRESUMEN
Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
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Antibacterianos/uso terapéutico , Doxiciclina/uso terapéutico , Hígado/inmunología , Pulmón/inmunología , Mitocondrias/metabolismo , Sepsis/tratamiento farmacológico , Tetraciclina/uso terapéutico , Animales , Proteínas de Ciclo Celular/genética , Modelos Animales de Enfermedad , Transporte de Electrón , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Microglia, the resident macrophages of the brain parenchyma, are key players in central nervous system (CNS) development, homeostasis, and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain quiescence following challenges remains less understood. Here, we explored the role of the interleukin-10 (IL-10) axis in restoring murine microglia homeostasis following a peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia displayed neuronal impairment and succumbed to fatal sickness. Addition of a microglial tumor necrosis factor (TNF) deficiency rescued these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing immune cells in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation.
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Endotoxinas/inmunología , Interleucina-10/metabolismo , Microglía/inmunología , Microglía/metabolismo , Animales , Biomarcadores , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Inmunofenotipificación , Interleucina-10/genética , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Lipopolisacáridos/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , RatonesRESUMEN
Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.