Diverse Immune Responses Mediated by Beta-Adrenergic and Corticotropin-Releasing Hormone Receptors in a Model of Pneumococcal sepsis




Kim, Byung-Jin


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Neuroendocrine stimulation can impact disease states by regulating immune function. The purpose of our studies was to define the functional role of stress-induced neuroendocrine factors, catecholamines and corticotropin-releasing hormone (CRH) on immune responses involved in the pathogenesis of Streptococcus pneumoniae (S. pneumoniae) infection implementing both in vitro and in vivo methodology. Dendritic cells play a pivotal role in antigen presentation and cytokine production, influencing both innate and adaptive immunity. Initial studies examined the potential immunomodulatory effect of epinephrine and CRH on DC cytokine production in response to the bacterial pathogenic ligand, lipopolysaccharide (LPS). In addition, the ability of DC to dictate CD4+ T cell activation as a consequence of CRH or epinephrine pre-treatment was examined using an in vitro co-culture system. Epinephrine and CRH pre-treatment resulted in a preferential increase in IL-23 and IL-10 cytokine production. In contrast, IL-12p70 was significantly attenuated in response to epinephrine and CRH pre-treatment. Preferences in IL-23 and IL-10 cytokine production by DC pre-treated with epinephrine and CRH corresponded with an increase in IL-4 and IL-17A, but not IFN-y cytokine production by CD4+ T cells. These results suggest that exposure to stress-derived epinephrine/CRH dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogen. Our second study examined the functional properties of IL-23 during pulmonary S. pneumoniae infection. IL-23 plays a crucial role in establishing host defenses against extracellular pathogens. Further investigation is still required to define the impact of IL-23 on acute pulmonary S. pneumoniae infection. Utilizing IL-23p19 genetic deficient mice, we determined bacterial load, cytokine production and the contribution of neutrophils against S. pneumoniae infection using monoclonal antibody-mediated systemic neutrophil depletion. The absence of IL-23 induced a higher bacterial load in lung and blood as compared to IL-23 competent counterparts. In the absence of IL-23, production of proinflammatory cytokines such as IL-6, IL-12p70 as well as IL-17A and IFN- were dampened as compared to wild type mice. In addition, neutrophil distribution was also altered in IL-23-deficient mice, suggesting impaired neutrophil recruitment into lung. Interestingly, neutrophil depletion did not impact bacterial load in lung and blood in both IL-23 competent and deficient mice. These findings, suggest a novel role of IL-23 in pulmonary S. pneumoniae infection, potentially independent of neutrophil function. We next examined the possible impact of CRH and catecholamines as regulators of immune function against acute bacterial infection in response to stress. Utilizing a murine model of acute pulmonary S. pneumoniae infection and restraint stress, we selectively blocked CRH receptors (CRHR1 and CRHR2) as well as the 2 adrenergic receptor prior to restraint stress followed by intranasal pulmonary S. pneumoniae infection. Antagonist administration did not impact restraint stress-induced physiological responses as compared to restraint stressed mice, which did not receive receptor antagonists. However, following S. pneumoniae infection, physiological changes including weight and temperature were altered in response to administration of selective CRH receptor and β2 adrenergic receptor antagonists. Survival rate, bacterial load and cytokine production corresponded with physiological differences observed in response to selective CRH receptor and 2 adrenergic receptor antagonists. Importantly, preferential differences in bacterial colonization and survival corresponded with distinct differences in inflammatory cytokine production and immune cell distribution along pulmonary airways. In particular, opposing effects in IL-17A and neutrophil accumulation was found among mice administered the CRHR1 versus the CRHR2 antagonists. Together, these findings indicate that activation of each receptor can influence immune responses against S. pneumoniae infection. Thus, our findings provide further understanding of how stress-derived neuroendocrine factors directly impact immune responses related to immunopathology and immunoprotection.