RESUMEN
Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of severe asthma patients was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4+ T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23 binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, and lymphocytes, IL-17+ CD4 T cells, mucous cell metaplasia and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19) (αIL-23) also decreased macrophages, IL-17+ CD4 T cells and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness, but did decrease lung neutrophils, macrophages, and IL-17+ CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5+ or IL-13+ CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation, and that these protective actions were broader than blocking only IL-17A or IL-5, which selectively decreased airway neutrophils and eosinophils, respectively.
RESUMEN
Inflammation is a protective host response essential for controlling viral replication and promoting tissue repair [...].
Asunto(s)
Inflamación , Virosis , Inflamación/virología , Humanos , Virosis/inmunología , Virosis/virología , Animales , Virus/inmunología , Virus/patogenicidad , Replicación Viral , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
Respiratory viral infections with influenza A virus (IAV) or respiratory syncytial virus (RSV) pose a significant threat to public health due to excess morbidity and mortality. Dysregulated and excessive inflammatory responses are major underlying causes of viral pneumonia severity and morbidity, including aberrant host immune responses and increased risk for secondary bacterial infections. Currently available antiviral therapies have not substantially reduced the risk of severe viral pneumonia for these pathogens. Thus, new therapeutic approaches that can promote resolution of the pathogen-initiated inflammation without impairing host defense would represent a significant advance. Recent research has uncovered the potential for specialized pro-resolving mediators (SPMs) to transduce multipronged actions for the resolution of serious respiratory viral infection without increased risk for subsequent host susceptibility to bacterial infection. Here, we review recent advances in our understanding of SPM production and SPM receptor signaling in respiratory virus infections and the intriguing potential of harnessing SPM pathways to control excess morbidity and mortality from IAV and RSV pneumonia.
Asunto(s)
Neumonía Viral , Infecciones por Virus Sincitial Respiratorio , Humanos , Inflamación/metabolismo , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/metabolismo , Mediadores de Inflamación/metabolismoRESUMEN
Eosinophils (Eos) reside in multiple organs during homeostasis and respond rapidly to an inflammatory challenge. Although Eos share chemical staining properties, they also demonstrate phenotypic and functional plasticity that is not fully understood. Here, we used a murine model of allergic lung inflammation to characterize Eos subsets and determine their spatiotemporal and functional regulation during inflammation and its resolution in response to resolvin D2 (RvD2), a potent specialized proresolving mediator. Two Eos subsets were identified by CD101 expression with distinct anatomic localization and transcriptional signatures at baseline and during inflammation. CD101low Eos were predominantly located in a lung vascular niche and responded to allergen challenge by moving into the lung interstitium. CD101high Eos were predominantly located in bronchoalveolar lavage (BAL) and extravascular lung, only present during inflammation, and had transcriptional evidence for cell activation. RvD2 reduced total Eos numbers and changed their phenotype and activation by at least two distinct mechanisms: decreasing interleukin 5-dependent recruitment of CD101low Eos and decreasing conversion of CD101low Eos to CD101high Eos. Collectively, these findings indicate that Eos are a heterogeneous pool of cells with distinct activation states and spatiotemporal regulation during resolution of inflammation and that RvD2 is a potent proresolving mediator for Eos recruitment and activation.
Asunto(s)
Alveolitis Alérgica Extrínseca , Neumonía , Eosinofilia Pulmonar , Ratones , Animales , Eosinófilos/metabolismo , Líquido del Lavado Bronquioalveolar , Eosinofilia Pulmonar/metabolismo , Inflamación/metabolismo , Neumonía/metabolismo , FenotipoRESUMEN
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli-evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-ß levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ-/-) when compared to WT. In addition, GILZ-/- showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli-evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli.
Asunto(s)
Infecciones por Escherichia coli , Peritonitis , Factores de Transcripción , Animales , Ratones , Escherichia coli/metabolismo , Infecciones por Escherichia coli/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Peritonitis/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.
Asunto(s)
Trampas Extracelulares , Sepsis , Ratones , Animales , Fibrinolisina , Plasminógeno , Trampas Extracelulares/metabolismo , Interleucina-6/metabolismo , Inflamación/metabolismo , Sepsis/metabolismo , Fibrina/metabolismoRESUMEN
Knee injury negatively impacts routine activities and quality of life of millions of people every year. Disruption of tendons, ligaments, and articular cartilage are major causes of knee lesions, leading to social and economic losses. Besides the attempts for an optimal recovery of knee function after surgery, the joint healing process is not always adequate given the nature of intra-articular environment. Based on that, different therapeutic methods attempt to improve healing capacity. Hyperbaric oxygen therapy (HBOT) is an innovative biophysical approach that can be used as an adjuvant treatment post-knee surgery, to potentially prevent chronic disorders that commonly follows knee injuries. Given the well-recognized role of HBOT in improving wound healing, further research is necessary to clarify the benefits of HBOT in damaged musculoskeletal tissues, especially knee disorders. Here, we review important mechanisms of action for HBOT-induced healing including the induction of angiogenesis, modulation of inflammation and extracellular matrix components, and activation of parenchyma cells-key events to restore knee function after injury. This review discusses the basic science of the healing process in knee injuries, the role of oxygen during cicatrization, and shed light on the promising actions of HBOT in treating knee disorders, such as tendon, ligament, and cartilage injuries.
Asunto(s)
Oxigenoterapia Hiperbárica , Traumatismos de la Rodilla , Cicatrización de Heridas , Humanos , Enfermedad Crónica/prevención & control , Traumatismos de la Rodilla/complicaciones , Traumatismos de la Rodilla/terapia , Calidad de Vida , Cicatrización de Heridas/fisiología , Neovascularización Fisiológica , Matriz Extracelular , Inflamación , Oxígeno/metabolismoRESUMEN
The resolution of infection is an active process with specific molecular and cellular mechanisms that temper inflammation and enhance pathogen clearance. Here, the specialized pro-resolving mediator (SPM) Maresin 1 (MaR1) inhibited respiratory syncytial virus (RSV)-induced inflammation. inlerleukin-13 production from type 2 innate lymphoid cells (ILC) and CD4 T helper type 2 cells was decreased by exogenous MaR1. In addition, MaR1 increased amphiregulin production and decreased RSV viral transcripts to promote resolution. MaR1 also promoted interferon-ß production in mouse lung tissues and also in pediatric lung slices. MaR1 significantly inhibited the RSV-triggered aberrant inflammatory phenotype in FoxP3-expressing Tregs. The receptor for MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was constitutively expressed on Tregs. Following RSV infection, mice lacking Lgr6 had exacerbated type 2 immune responses with an increased viral burden and blunted responses to MaR1. Together, these findings have uncovered a multi-pronged protective signaling axis for MaR1-Lgr6, improving Tregs's suppressive function and upregulating host antiviral genes resulting in decreased viral burden and pathogen-mediated inflammation, ultimately promoting restoration of airway mucosal homeostasis.
Asunto(s)
Neumonía Viral , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Ratones , Animales , Inmunidad Innata , Linfocitos , Inflamación , Ácidos Docosahexaenoicos/farmacología , Receptores Acoplados a Proteínas GRESUMEN
COVID-19 is a multisystem disease caused by SARS-CoV-2 and is associated with an imbalance between the coagulation and fibrinolytic systems. Overall, hypercoagulation, hypofibrinolysis and fibrin-clot resistance to fibrinolysis predispose patients to thrombotic and thromboembolic events. In the lungs, the virus triggers alveolar and interstitial fibrin deposition, endothelial dysfunction, and pulmonary intravascular coagulation, all events intrinsically associated with the activation of inflammation and organ injury. Adding to the pathogenesis of COVID-19, there is a positive feedback loop by which local fibrin deposition in the lungs can fuel inflammation and consequently dysregulates coagulation, a process known as immunothrombosis. Therefore, fibrinolysis plays a central role in maintaining hemostasis and tissue homeostasis during COVID-19 by cleaning fibrin clots and controlling feed-forward products of coagulation. In addition, components of the fibrinolytic system have important immunomodulatory roles, as evidenced by studies showing the contribution of Plasminogen/Plasmin (Plg/Pla) to the resolution of inflammation. Herein, we review clinical evidence for the dysregulation of the fibrinolytic system and discuss its contribution to thrombosis risk and exacerbated inflammation in severe COVID-19. We also discuss the current concept of an interplay between fibrinolysis and inflammation resolution, mirroring the well-known crosstalk between inflammation and coagulation. Finally, we consider the central role of the Plg/Pla system in resolving thromboinflammation, drawing attention to the overlooked consequences of COVID-19-associated fibrinolytic abnormalities to local and systemic inflammation.
Asunto(s)
COVID-19 , Trombosis , Humanos , Inflamación/tratamiento farmacológico , COVID-19/complicaciones , SARS-CoV-2 , Trombosis/etiologíaRESUMEN
Bone marrow transplantation (BMT) involves conditioning regimens which acutely induce side effects, including systemic inflammation, intestinal damage and shifts in the gut microbial composition, some of which may persist chronically. As the gut microbiota affect systemic immune responses, we aimed to investigate whether, post-BMT, the peripheral immune system is modulated as a direct consequence of alterations in the gut microbiota. We show that 24 weeks post-BMT, splenocytes but not peritoneal macrophages display increased cytokine response patterns upon ex-vivo stimulation with various pathogens as compared to untreated controls. The pattern of BMT-induced cytokine responses was transferred to splenocytes, and not to peritoneal macrophages, of healthy controls via co-housing and transferred to germfree mice via transplantation of cecum content. Thus, BMT induces changes in gut microbiota that in their turn increase cytokine responsiveness of splenocytes. Thus, BMT establishes a dominant microbiota that attenuates normalization of the immune-response.
Asunto(s)
Microbioma Gastrointestinal , Animales , Trasplante de Médula Ósea/efectos adversos , Citocinas , Sistema Inmunológico , Ratones , BazoRESUMEN
Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ-/-) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ-/- macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae-infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections.
Asunto(s)
Neumonía Neumocócica , Animales , Glucocorticoides/farmacología , Inflamación/metabolismo , Leucina Zippers , Ratones , Neumonía Neumocócica/complicaciones , Neumonía Neumocócica/tratamiento farmacológico , Streptococcus pneumoniae/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.
Asunto(s)
Angiotensina I , Macrófagos , Monocitos , Fragmentos de Péptidos , Fagocitosis , Proto-Oncogenes Mas/metabolismo , Angiotensina I/metabolismo , Angiotensina I/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Monocitos/fisiología , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Peritonitis , Fagocitosis/efectos de los fármacos , Fagocitosis/fisiología , Fenotipo , Receptores CCR2/metabolismoRESUMEN
Along with respiratory tract disease per se, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.
Asunto(s)
Infecciones por Enterobacteriaceae/etiología , Ácidos Grasos Volátiles/biosíntesis , Interacciones Huésped-Patógeno , Virus de la Influenza A/fisiología , Gripe Humana/complicaciones , Gripe Humana/virología , Mucosa Intestinal/metabolismo , Interacciones Microbianas , Susceptibilidad a Enfermedades , Disbiosis , Infecciones por Enterobacteriaceae/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Gripe Humana/metabolismo , Mucosa Intestinal/inmunologíaRESUMEN
For decades, glucocorticoids (GC) have been used to treat several inflammatory conditions, including chronic and autoimmune diseases, due to their potent anti-inflammatory properties. In the context of infectious diseases, the use of GCs may be effective as adjuvant to antibiotic therapy by controlling excessive inflammatory responses resulting in better outcome in some cases. However, the use of GCs has been associated with a vast number of side effects, including increased probability of immunosuppression and consequent risk of opportunistic infection. Glucocorticoid-induced leucine zipper (GILZ) and Annexin A1 (AnxA1) are GC-induced proteins intrinsically involved with the anti-inflammatory functions of GCs without the associated adverse metabolic effects. Recent studies have shown that these GC-proteins exhibit pro-resolving effects. An essential characteristic of pro-resolving molecules is their ability to coordinate the resolution of inflammation and promote host defense in most experimental models of infection. Although the role of GILZ and AnxA1 in the context of infectious diseases remain to be better explored, herein we provide an overview of the emerging functions of these GC-proteins obtained from pre-clinical models of infectious diseases.
Asunto(s)
Anexina A1/metabolismo , Antiinflamatorios/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Inflamación/tratamiento farmacológico , Enfermedades Parasitarias/tratamiento farmacológico , Factores de Transcripción/metabolismo , Virosis/tratamiento farmacológico , Animales , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Interacciones Huésped-Patógeno , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Enfermedades Parasitarias/inmunología , Enfermedades Parasitarias/metabolismo , Enfermedades Parasitarias/parasitología , Inducción de Remisión , Transducción de Señal , Resultado del Tratamiento , Virosis/inmunología , Virosis/metabolismo , Virosis/virologíaRESUMEN
Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated with secondary pneumococcal infection. Therapeutic strategies based on pro-resolving molecules have great potential against acute inflammatory diseases. Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator that acts on its Mas receptor (MasR) to promote resolution of inflammation. We investigated the effects of Ang-(1-7) and the role of MasR in the context of primary IAV infection and secondary pneumococcal infection and evaluated pulmonary inflammation, virus titers and bacteria counts, and pulmonary damage. Therapeutic treatment with Ang-(1-7) decreased neutrophil recruitment, lung injury, viral load and morbidity after a primary IAV infection. Ang-(1-7) induced apoptosis of neutrophils and efferocytosis of these cells by alveolar macrophages, but had no direct effect on IAV replication in vitro. MasR-deficient (MasR-/-) mice were highly susceptible to IAV infection, displaying uncontrolled inflammation, increased viral load and greater lethality rate, as compared to WT animals. Ang-(1-7) was not protective in MasR-/- mice. Interestingly, Ang-(1-7) given during a sublethal dose of IAV infection greatly reduced morbidity associated with a subsequent S. pneumoniae infection, as seen by decrease in the magnitude of neutrophil influx, number of bacteria in the blood leading to a lower lethality. Altogether, these results show that Ang-(1-7) is highly protective against severe primary IAV infection and protects against secondary bacterial infection of the lung. These effects are MasR-dependent. Mediators of resolution of inflammation, such as Ang-(1-7), should be considered for the treatment of pulmonary viral infections.
Asunto(s)
Angiotensina I/uso terapéutico , Antiinflamatorios/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Infecciones Neumocócicas/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Proteínas Proto-Oncogénicas/inmunología , Receptores Acoplados a Proteínas G/inmunología , Células A549 , Angiotensina I/farmacología , Animales , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/inmunología , Perros , Humanos , Virus de la Influenza A , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Células de Riñón Canino Madin Darby , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Fragmentos de Péptidos/farmacología , Peroxidasa/inmunología , Fagocitosis/efectos de los fármacos , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/patología , Neumonía Viral/inmunología , Neumonía Viral/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Receptores Acoplados a Proteínas G/genética , Streptococcus pneumoniaeRESUMEN
A complex intracellular signaling governs different cellular responses in inflammation. Extracellular stimuli are sensed, amplified, and transduced through a dynamic cellular network of messengers converting the first signal into a proper response: production of specific mediators, cell activation, survival, or death. Several overlapping pathways are coordinated to ensure specific and timely induction of inflammation to neutralize potential harms to the tissue. Ideally, the inflammatory response must be controlled and self-limited. Resolution of inflammation is an active process that culminates with termination of inflammation and restoration of tissue homeostasis. Comparably to the onset of inflammation, resolution responses are triggered by coordinated intracellular signaling pathways that transduce the message to the nucleus. However, the key messengers and pathways involved in signaling transduction for resolution are still poorly understood in comparison to the inflammatory network. cAMP has long been recognized as an inducer of anti-inflammatory responses and cAMP-dependent pathways have been extensively exploited pharmacologically to treat inflammatory diseases. Recently, cAMP has been pointed out as coordinator of key steps of resolution of inflammation. Here, we summarize the evidence for the role of cAMP at inducing important features of resolution of inflammation.
Asunto(s)
AMP Cíclico/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Sistemas de Mensajero Secundario , Animales , Apoptosis , Quimiotaxis de Leucocito , Granulocitos/inmunología , Granulocitos/metabolismo , Granulocitos/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Fagocitosis , FenotipoRESUMEN
The average respiration rate for an adult is 12-20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common feature - airway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs.
Asunto(s)
Granulocitos/efectos de los fármacos , Fármacos del Sistema Respiratorio/uso terapéutico , Sistema Respiratorio/efectos de los fármacos , Enfermedades Respiratorias/tratamiento farmacológico , Animales , Quimiotaxis de Leucocito/efectos de los fármacos , Granulocitos/inmunología , Granulocitos/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Terapia Molecular Dirigida , Fenotipo , Sistema Respiratorio/inmunología , Sistema Respiratorio/metabolismo , Sistema Respiratorio/fisiopatología , Fármacos del Sistema Respiratorio/efectos adversos , Enfermedades Respiratorias/inmunología , Enfermedades Respiratorias/metabolismo , Enfermedades Respiratorias/fisiopatología , Transducción de SeñalRESUMEN
Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection.
Asunto(s)
Disbiosis/microbiología , Ácidos Grasos Volátiles/biosíntesis , Tracto Gastrointestinal/microbiología , Gripe Humana/microbiología , Pulmón/microbiología , Infecciones Neumocócicas/complicaciones , Sobreinfección/complicaciones , Sobreinfección/microbiología , Acetatos/farmacología , Animales , Disbiosis/complicaciones , Disbiosis/virología , Conducta Alimentaria , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Ratones Endogámicos C57BL , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/virología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses, and return to lung homeostasis. However, an exaggerated immune response, characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. We investigated the role of ACKR2 during IAV infection in mice. Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2-/-) mice were protected from IAV, presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B lymphocytes, formation of inducible bronchus-associated lymphoid tissue and production of IgA in the airways of ACKR2-/- mice post-IAV. CCL5 neutralization in ACKR2-/- mice prevented lymphocyte recruitment and increased bronchoalveolar lavage fluid protein levels and pulmonary dysfunction. Finally, CCR5-/- mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5+ T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice.
Asunto(s)
Linfocitos B/metabolismo , Quimiocina CCL5/metabolismo , Pulmón/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Receptores CCR5/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B/virología , Líquido del Lavado Bronquioalveolar/virología , Virus de la Influenza A/patogenicidad , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/virología , Linfocitos T Reguladores/virologíaRESUMEN
Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.