Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

Balance between protective and pathogenic immune responses to pneumonia in the neonatal lung enforced by gut microbiota.

While modern clinical practices like cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure, mirroring current clinical practices, interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system as assessed by single-cell proteomic and transcriptomic analyses of the pulmonary immune response. Early-life antibiotic exposure rendered newborn macaques susceptible to bacterial pneumonia, mediated by profound changes in neutrophil senescence, inflammatory signaling, and macrophage dysfunction. Pathogenic reprogramming of pulmonary immunity was reflected by a hyperinflammatory signature in all pulmonary immune cell subsets. Distinct patterns of immunoparalysis, including dysregulated antigen presentation in alveolar macrophages, impaired costimulatory function in T helper cells, and dysfunctional cytotoxic responses in natural killer (NK) cells, were coupled with a global loss of tissue-protective, homeostatic pathways in lungs of dysbiotic newborns. Fecal microbiota transfer corrected the broad immune maladaptations and protected against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity. Gut microbiota promote balance between pathways driving tissue repair and inflammatory responses, thereby leading to clinical recovery from infection in infants.

Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion withStreptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp−/−) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Alterations of the pulmonary immunity are independent of spontaneous pneumonia in an experimental model of ischemic stroke

Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multi-factorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies of focal ischemic stroke induction, using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that severe brain damage results in massive apoptosis and functional defects of lymphocytes in the spleen, thymus, and peripheral blood. However, how immune alternations in remote tissues lead to a greater susceptibility to lung infections is not well-understood. Importantly, how ischemic stroke alters immune-cell fates, and the expression of cytokines and chemokines in the lungs that directly impact pulmonary immunity, has not been characterized. We report here that ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells (DCs), but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, and eosinophils in the lungs. The depletion of immune cells in the lungs is not caused by apoptosis, cell infiltration to the brain, or spontaneous pneumonia following ischemic stroke as previously described, but correlates with a significant reduction in the levels of multiple chemokines in the lungs, including: CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. These findings suggest that ischemic stroke negatively impacts pulmonary immunity to become more susceptible for SAP development. Further investigation into the mechanisms that control pulmonary immune alternations following ischemic stroke may identify novel diagnostic or therapeutic targets for SAP.