RESUMEN
Rationale: Platelets are generated in the capillaries of the lung, control hemostasis, and display immunological functions. Tuberculosis primarily affects the lung, and patients show platelet changes and hemoptysis. A role of platelets in immunopathology of pulmonary tuberculosis requires careful assessment.Objectives: To identify the dynamics and interaction partners of platelets in the respiratory tissue and establish their impact on the outcome of pulmonary tuberculosis.Methods: Investigations were primarily performed in murine models of primary progressive pulmonary tuberculosis, by analysis of mouse strains with variable susceptibility to Mycobacterium tuberculosis infection using platelet depletion and delivery of antiplatelet drugs.Measurements and Main Results: Platelets were present at the site of infection and formed aggregates with different myeloid subsets during experimental tuberculosis. Such aggregates were also detected in patients with tuberculosis. Platelets were detrimental during the early phase of infection, and this effect was uncoupled from their canonical activation. Platelets left lung cell dynamics and patterns of antimycobacterial T-cell responses unchanged but hampered antimicrobial defense by restricting production of reactive oxygen species in lung-residing myeloid cells.Conclusions: Platelets are detrimental in primary progressive pulmonary tuberculosis, orchestrate lung immunity by modulating innate immune responsiveness, and may be amenable to new interventions for this deadly disease.
Asunto(s)
Plaquetas/metabolismo , Mycobacterium tuberculosis/inmunología , Fagocitos/patología , Estallido Respiratorio/fisiología , Linfocitos T/inmunología , Tuberculosis Pulmonar/metabolismo , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Masculino , Ratones , Ratones Endogámicos C57BL , Fagocitos/metabolismo , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/patologíaRESUMEN
General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation.
Asunto(s)
Interferón Tipo I/inmunología , Pulmón/inmunología , Fagocitos/inmunología , Transducción de Señal/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Células Cultivadas , Quimiocina CXCL1/inmunología , Quimiocina CXCL5/inmunología , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Neutrófilos/inmunología , Alveolos Pulmonares/inmunología , Receptor de Interferón alfa y beta/inmunología , Linfocitos T/inmunologíaRESUMEN
The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223(/) mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223(/) animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.
Asunto(s)
MicroARNs/genética , MicroARNs/inmunología , Infiltración Neutrófila/genética , Tuberculosis Pulmonar/genética , Animales , Quimiocina CCL3/metabolismo , Quimiocina CXCL2/metabolismo , Susceptibilidad a Enfermedades , Humanos , Inmunidad Innata/genética , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/sangre , Infiltración Neutrófila/inmunología , Receptores de Interleucina-8B/deficiencia , Receptores de Interleucina-8B/genética , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/patología , Regulación hacia ArribaRESUMEN
As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1ß in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1ß in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1-independent IL-1ß release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.