Mechanisms of social-stress enhanced allergic airway response in a mouse model

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DESCRIPTION (provided by applicant): Chronic psychosocial stress alters susceptibility to various infectious and inflammatory disorders and enhances the asthmatic airway response. Although hypothalamic-pituitary-adrenal axis activation during stress has long been recognized, the role of endogenous glucocorticoids in regulating the pulmonary immune response remains unclear. Our preliminary studies showed that development of allergic airway inflammation upon inhalation of allergen is protected by homeostatic mechanisms modulating airway dendritic cell function through the lung collectin, surfactant protein D (SP-D). We hypothesize that corticosteroid insensitivity of myeloid dendritic cells (due to cell-type specific impairment of GR expression and abnormal interactions between the GR and NF-?B) mediate the enhancing effects of stress on allergic airway inflammation. Altered GR function attenuates the protective raise in SP-D synthesis in epithelial cells, in response to allergen inhalation. This effect in turn further amplifies dendritic and T cell activation, perpetuating the inflammatory airway response. Aim 1 is to define how stress-induced corticosteroid insensitivity in lung dendritic cells and T cells alter the allergic airway changes in vivo. Using GR agonists, antagonists and CRH-/- mice in a combination of social disruption stress (SDR) and allergic airway inflammation we will test the hypothesis that social stress- induced enhancement of allergic airway inflammation is in part, mediated by corticosteroid insensitive dendritic and/or T cells. By investigating GR and NF-?B expression and DNA binding in corticosterone treated dendritic and T cells, we will define whether corticosteroid insensitivity requires GR downregulation and/or an abnormal NF-?B-GR "tethering". Aim 2 will test the hypotheses that stress attenuates the increase in SP-D transcription in response to allergen challenge and that SP-D protects against development of Th2- type inflammation by inhibiting differentiation and activation of myeloid dendritic cells. By investigating GR, C/EBP and STAT interactions in type II alveolar epithelial cells, we will determine whether stress-induced changes in corticosteroid function affect SP-D transcription. Using conditional SP-D expressor mice we will define if lack of SP-D predisposes to and SP-D over expression protects against the stress-induced enhancement of the allergic airway response. By studying the effects of a recombinant mutant SP-D containing the carbohydrate recognition (CRD), but not the collagen domain, and blocking antibodies against the negative Signal-Regulatory Protein (SIRP) on antigen presenting and Th cell function, we will test the hypothesis that CRD-SIRPa ligation is required for the inhibitory effects of SP-D. Elucidation of the importance of stress-induced impairment of GR and SP-D regulation has great clinical relevance since potentially novel approaches can be devised to control the allergic immune response in the lung.