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1.
Nat Immunol ; 19(4): 327-341, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29507356

RESUMEN

Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.


Asunto(s)
Inmunidad Innata/inmunología , Heridas y Lesiones/inmunología , Animales , Humanos
2.
Immunity ; 47(1): 3-5, 2017 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-28723551

RESUMEN

Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. In this issue of Immunity, Roquilly et al. (2017) show that dendritic cells and macrophages developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections.


Asunto(s)
Tolerancia Inmunológica , Sepsis/inmunología , Células Dendríticas/inmunología , Humanos , Terapia de Inmunosupresión , Macrófagos/inmunología
3.
Proc Natl Acad Sci U S A ; 120(40): e2215421120, 2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37756334

RESUMEN

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFß and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly (P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls (n = 10). The pulmonary sources of externalized histones were Ly6G+CD11b+ neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFß1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM+ cells to antagonize macrophage-derived IL-27 production. TGFß1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFß1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.


Asunto(s)
Fibrosis Pulmonar Idiopática , Interleucina-27 , Humanos , Ratones , Animales , Ratones Endogámicos C57BL , Histonas , Plaquetas , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética
4.
Int J Mol Sci ; 25(16)2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39201339

RESUMEN

In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone-TLR interactions and their mechanisms.


Asunto(s)
Histonas , Ratones Noqueados , Animales , Histonas/metabolismo , Ratones , Receptores Toll-Like/metabolismo , Masculino , Sepsis/metabolismo , Sepsis/complicaciones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Corazón/fisiopatología
5.
Immunity ; 39(5): 801-2, 2013 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-24238336

RESUMEN

Special proresolving mediators (SPMs) limit the intensity of inflammation; however, their regulation is poorly understood. In this issue of Immunity, Li et al. (2013) describe bipolar roles for miR-466l in the promotion of inflammation and the induction of SPMs.


Asunto(s)
Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , MicroARNs/fisiología , Neutrófilos/metabolismo , Peritonitis/metabolismo , Sepsis/sangre , Animales , Humanos , Masculino
6.
J Immunol ; 205(1): 251-260, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32444389

RESUMEN

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.


Asunto(s)
Lesión Pulmonar Aguda/inmunología , Cardiomiopatías/inmunología , Coinfección/inmunología , Complemento C6/metabolismo , Inmunidad Innata , Sepsis/inmunología , Lesión Pulmonar Aguda/diagnóstico , Lesión Pulmonar Aguda/patología , Animales , Cardiomiopatías/diagnóstico , Cardiomiopatías/patología , Coinfección/complicaciones , Coinfección/diagnóstico , Coinfección/patología , Complemento C6/genética , Modelos Animales de Enfermedad , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Sepsis/complicaciones , Sepsis/diagnóstico , Sepsis/genética , Índice de Severidad de la Enfermedad
7.
J Immunol ; 202(3): 931-942, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30578307

RESUMEN

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.


Asunto(s)
Diabetes Mellitus Experimental/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Inmunidad Innata/efectos de los fármacos , Obesidad/inmunología , Sepsis/inmunología , Animales , Bacterias , Citocinas/genética , Citocinas/inmunología , Diabetes Mellitus Experimental/microbiología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Monocitos/patología , Neutrófilos/inmunología , Neutrófilos/patología , Obesidad/microbiología , Fagocitosis , Sepsis/tratamiento farmacológico , Sepsis/microbiología
8.
Immunol Rev ; 274(1): 330-353, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27782333

RESUMEN

Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.


Asunto(s)
Sistema Inmunológico , Inmunidad , Inmunomodulación , Inflamación/inmunología , Sepsis/inmunología , Animales , Progresión de la Enfermedad , Humanos , Terapia de Inmunosupresión , Inflamación/terapia , Prevención Secundaria , Sepsis/terapia , Factores de Tiempo , Resultado del Tratamiento
9.
FASEB J ; 31(9): 4129-4139, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28572445

RESUMEN

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.


Asunto(s)
Complemento C5a/metabolismo , Regulación de la Expresión Génica/fisiología , Cardiopatías/etiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sepsis/metabolismo , Animales , Complemento C5a/genética , Cardiopatías/metabolismo , Interleucinas , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Ratas Sprague-Dawley , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/metabolismo
10.
J Immunol ; 197(6): 2353-61, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27521340

RESUMEN

There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E' septal annulus, E/E' septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na(+)/Ca(2+) exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.


Asunto(s)
Coinfección/inmunología , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/patología , Sepsis/inmunología , Sepsis/fisiopatología , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/inmunología , Coinfección/microbiología , Coinfección/fisiopatología , Complemento C5a/inmunología , Citoplasma/química , Citoplasma/metabolismo , Corazón/fisiopatología , Ratones , Miocitos Cardíacos/microbiología , Receptor de Anafilatoxina C5a/deficiencia , Receptor de Anafilatoxina C5a/inmunología , Receptor de Anafilatoxina C5a/fisiología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/inmunología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Sepsis/complicaciones
11.
PLoS Pathog ; 11(9): e1005140, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26402732

RESUMEN

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.


Asunto(s)
Complemento C5a/metabolismo , Interacciones Huésped-Parásitos , Malaria/fisiopatología , Trastornos Neurocognitivos/etiología , Neurogénesis , Complicaciones Parasitarias del Embarazo/fisiopatología , Receptor de Anafilatoxina C5a/metabolismo , Animales , Aminas Biogénicas/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Circulación Cerebrovascular , Regulación hacia Abajo , Femenino , Desarrollo Fetal , Malaria/inmunología , Malaria/metabolismo , Malaria/parasitología , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/patología , Neuronas/inmunología , Neuronas/metabolismo , Neuronas/patología , Plasmodium berghei/inmunología , Plasmodium berghei/fisiología , Embarazo , Complicaciones Parasitarias del Embarazo/inmunología , Complicaciones Parasitarias del Embarazo/metabolismo , Complicaciones Parasitarias del Embarazo/parasitología , Receptor de Anafilatoxina C5a/genética , Transducción de Señal
12.
FASEB J ; 30(12): 3997-4006, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27543123

RESUMEN

Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from sham-procedure mice contained high mRNA levels of NLRP3 and IL-1ß. Using the inflammasome protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature IL-1ß. Immunostaining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and IL-1ß proteins in CMs. CLP caused substantial increases in mRNAs for IL-1ß and NLRP3 in CMs which are reduced in the absence of either C5aR1 or C5aR2. After CLP, NLRP3-/- mice showed reduced plasma levels of IL-1ß and IL-6. In vitro exposure of wild-type CMs to recombinant C5a (rC5a) caused elevations in both cytosolic and nuclear/mitochondrial reactive oxygen species (ROS), which were C5a-receptor dependent. Use of a selective NOX2 inhibitor prevented increased cytosolic and nuclear/mitochondrial ROS levels and release of IL-1ß. Finally, NLRP3-/- mice had reduced defects in echo/Doppler parameters in heart after CLP. These studies establish that the NLRP3 inflammasome contributes to the cardiomyopathy of polymicrobial sepsis.-Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huber-Lang, M., Russell, M. W., Ward, P. A. Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis.


Asunto(s)
Complemento C5a/metabolismo , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sepsis/metabolismo , Animales , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones , Ratas , Especies Reactivas de Oxígeno/metabolismo
13.
J Immunol ; 194(3): 868-72, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25539817

RESUMEN

In the early stages of sepsis, lymphocytes undergo apoptosis, resulting in lymphopenia and immunosuppression. The trigger for septic lymphopenia is unknown. Using the polymicrobial model of murine sepsis, we investigated the role of C5a receptors in septic lymphopenia. In wild-type mice, cecal ligation and puncture resulted in splenocyte apoptosis and significant lymphopenia after 3 d, which was not observed in C5aR1(-/-) or C5aR2(-/-) mice. Our data show that mouse neutrophils exposed to recombinant mouse C5a cause release of histones in a dose-dependent and time-dependent manner. Histone levels in spleen were significantly elevated following cecal ligation and puncture but were reduced by the absence of C5aR1. Histones induced significant lymphocyte apoptosis in vitro. Ab-mediated neutralization of histones prevented the development of lymphopenia in sepsis. Together, these results describe a new pathway of septic lymphopenia involving complement and extracellular histones. Targeting of this pathway may have therapeutic benefit for patients with sepsis or other serious illness.


Asunto(s)
Linfopenia/etiología , Linfopenia/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Sepsis/complicaciones , Animales , Apoptosis , Complemento C5a/inmunología , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Espacio Extracelular , Histonas/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptor de Anafilatoxina C5a/genética
14.
Trends Immunol ; 34(3): 129-36, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23036432

RESUMEN

The pathophysiology of sepsis and its accompanying systemic inflammatory response syndrome (SIRS) and the events that lead to multiorgan failure and death are poorly understood. It is known that, in septic humans and rodents, the development of SIRS is associated with a loss of the redox balance, but SIRS can also develop in noninfectious states. In addition, a hyperinflammatory state develops, together with impaired innate immune functions of phagocytes, immunosuppression, and complement activation, collectively leading to septic shock and lethality. Here, we discuss recent insights into the signaling pathways in immune and phagocytic cells that underlie sepsis and SIRS and consider how these might be targeted for therapeutic interventions to reverse or attenuate pathways that lead to lethality during sepsis.


Asunto(s)
Inflamación , Sepsis/inmunología , Sepsis/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica , Animales , Citocinas/sangre , Humanos , Inflamación/inmunología , Inflamación/fisiopatología , Fagocitosis , Sepsis/complicaciones , Transducción de Señal , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología
15.
FASEB J ; 29(9): 3762-72, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25999468

RESUMEN

Excessive activation of the complement system is detrimental in acute inflammatory disorders. In this study, we analyzed the role of complement-derived anaphylatoxins in the pathogenesis of experimental acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in C57BL/6J mice. Intratracheal administration of recombinant mouse complement component (C5a) caused alveolar inflammation with abundant recruitment of Ly6-G(+)CD11b(+) leukocytes to the alveolar spaces and severe alveolar-capillary barrier dysfunction (C5a-ALI; EC(50[C5a]) = 20 ng/g body weight). Equimolar concentrations of C3a or desarginated C5a (C5a(desArg)) did not induce alveolar inflammation. The severity of C5a-ALI was aggravated in C5-deficient mice. Depletion of Ly6-G(+) cells and use of C5aR1(-/-) bone marrow chimeras suggested an essential role of C5aR1(+) hematopoietic cells in C5a-ALI. Blockade of PI3K/Akt and MEK1/2 kinase pathways completely abrogated lung injury. The mechanistic description is that C5a altered the alveolar cytokine milieu and caused significant release of CC-chemokines. Mice with genetic deficiency of CC-chemokine receptor (CCR) type 5, the common receptor of chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5, displayed reduced lung damage. Moreover, treatment with a CCR5 antagonist, maraviroc, was protective against C5a-ALI. In summary, our results suggest that the detrimental effects of C5a in this model are partly mediated through CCR5 activation downstream of C5aR1, which may be evaluated for potential therapeutic exploitation in ALI/ARDS.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Activación de Complemento , Complemento C3a/metabolismo , Complemento C5a des-Arginina/metabolismo , Alveolos Pulmonares/metabolismo , Receptores CCR5/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/patología , Animales , Antagonistas de los Receptores CCR5/farmacología , Complemento C3a/genética , Complemento C5a des-Arginina/genética , Ciclohexanos/farmacología , Leucocitos/metabolismo , Leucocitos/patología , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/genética , MAP Quinasa Quinasa 2/metabolismo , Maraviroc , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Alveolos Pulmonares/patología , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/metabolismo , Receptores CCR5/genética , Triazoles/farmacología
16.
FASEB J ; 29(5): 2185-93, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25681459

RESUMEN

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca(2+)]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca(2+)]i, as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.


Asunto(s)
Cardiomiopatías/etiología , Modelos Animales de Enfermedad , Histonas/efectos adversos , Mitocondrias/patología , Sepsis/complicaciones , Animales , Calcio/metabolismo , Cardiomiopatías/sangre , Cardiomiopatías/diagnóstico , Proteínas Portadoras/fisiología , Caspasa 1/fisiología , Células Cultivadas , Histonas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Sepsis/sangre , Sepsis/patología , Receptor Toll-Like 2/fisiología , Receptor Toll-Like 4/fisiología
17.
J Pineal Res ; 60(4): 405-14, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26888116

RESUMEN

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1ß and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.


Asunto(s)
Lesión Pulmonar Aguda/patología , Antiinflamatorios/farmacología , Inflamasomas/efectos de los fármacos , Melatonina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lesión Pulmonar Aguda/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inflamasomas/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Microtomografía por Rayos X
18.
J Immunol ; 192(12): 5974-83, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24795455

RESUMEN

The inflammasome is a key factor in innate immunity and senses soluble pathogen and danger-associated molecular patterns as well as biological crystals (urate, cholesterol, etc.), resulting in expression of IL-1ß and IL-18. Using a standard model of acute lung injury (ALI) in mice featuring airway instillation of LPS, ALI was dependent on availability of NLRP3 as well as caspase-1, which are known features of the NLRP3 inflammasome. The appearance of IL-1ß, a product of NLRP3 inflammasome activation, was detected in bronchoalveolar lavage fluids (BALF) in a macrophage- and neutrophil-dependent manner. Neutrophil-derived extracellular histones appeared in the BALF during ALI and directly activated the NLRP3 inflammasome. Ab-mediated neutralization of histones significantly reduced IL-1ß levels in BALF during ALI. Inflammasome activation by extracellular histones in LPS-primed macrophages required NLRP3 and caspase-1 as well as extrusion of K(+), increased intracellular Ca(2+) concentration, and generation of reactive oxygen species. NLRP3 and caspase-1 were also required for full extracellular histone presence during ALI, suggesting a positive feedback mechanism. Extracellular histone and IL-1ß levels in BALF were also elevated in C5a-induced and IgG immune complex ALI models, suggesting a common inflammatory mechanism. These data indicate an interaction between extracellular histones and the NLRP3 inflammasome, resulting in ALI. Such findings suggest novel targets for treatment of ALI, for which there is currently no known efficacious drug.


Asunto(s)
Lesión Pulmonar Aguda/inmunología , Proteínas Portadoras/inmunología , Inflamasomas/inmunología , Macrófagos Alveolares/inmunología , Neutrófilos/inmunología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/patología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Proteínas Portadoras/genética , Caspasa 1/genética , Caspasa 1/inmunología , Modelos Animales de Enfermedad , Histonas/genética , Histonas/inmunología , Inflamasomas/genética , Interleucina-18/genética , Interleucina-18/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Lipopolisacáridos/farmacología , Macrófagos Alveolares/patología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Neutrófilos/patología
19.
J Immunol ; 193(11): 5668-77, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25348624

RESUMEN

Severe sepsis and septic shock are leading causes of morbidity and mortality worldwide. Infection-associated inflammation promotes the development and progression of adverse outcomes in sepsis. The effects of heterodimeric IL-27 (p28/EBI3) have been implicated in the natural course of sepsis, whereas the molecular mechanisms underlying the regulation of gene expression and release of IL-27 in sepsis are poorly understood. We studied the events regulating the p28 subunit of IL-27 in endotoxic shock and polymicrobial sepsis following cecal ligation and puncture. Neutralizing Abs to IL-27(p28) improved survival rates, restricted cytokine release, and reduced bacterial burden in C57BL/6 mice during sepsis. Genetic disruption of IL-27 signaling enhanced the respiratory burst of macrophages. Experiments using splenectomized mice or treatment with clodronate liposomes suggested that macrophages in the spleen may be a significant source of IL-27(p28) during sepsis. In cultures of TLR4-activated macrophages, the frequency of F4/80(+)CD11b(+)IL-27(p28)(+) cells was reduced by the addition of IL-10. IL-10 antagonized both MyD88-dependent and TRIF-dependent release of IL-27(p28). Genetic deletion of STAT3 in Tie2-Cre/STAT3flox macrophages completely interrupted the inhibition of IL-27(p28) by IL-10 after TLR4 activation. In contrast, IL-10 remained fully active to suppress IL-27(p28) with deletion of SOCS3 in Tie2-Cre/SOCS3flox macrophages. Blockade of IL-10R by Ab or genetic deficiency of IL-10 resulted in 3-5-fold higher concentrations of IL-27(p28) in endotoxic shock and polymicrobial sepsis. Our studies identify IL-10 as a critical suppressing factor for IL-27(p28) production during infection-associated inflammation. These findings may be helpful for a beneficial manipulation of adverse IL-27(p28) release during sepsis.


Asunto(s)
Interleucina-10/metabolismo , Interleucinas/metabolismo , Macrófagos/fisiología , Factor de Transcripción STAT3/metabolismo , Sepsis/inmunología , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Anticuerpos Bloqueadores/administración & dosificación , Carga Bacteriana , Ciego/cirugía , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Interleucina-10/genética , Interleucinas/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Receptores de Citocinas/genética , Receptores de Interleucina , Factor de Transcripción STAT3/genética , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Receptor Toll-Like 4/inmunología
20.
Mediators Inflamm ; 2016: 1340156, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27382187

RESUMEN

C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1ß. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1ß during endotoxemia was reduced in C5aR1(-/-) mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1ß in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1ß expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1ß, which was accompanied by attenuated levels of pro-IL-1ß, NLRP3, and caspase-1 expression. C5a's suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1ß response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses.


Asunto(s)
Inflamasomas/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Animales , Western Blotting , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Complemento C5a/metabolismo , Complemento C5a/farmacología , Modelos Animales de Enfermedad , Endotoxemia/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inflamasomas/efectos de los fármacos , Interleucina-1beta/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptor de Anafilatoxina C5a/deficiencia , Receptor de Anafilatoxina C5a/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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