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.
Psychosocial stress has severe impact on the course of chronic asthma but the mechanisms are poorly defined. The broad objectives of this project are: 1. Validation of the importance of altered glucocorticoid responsiveness by immune cells and surfactant protein D (SP-D) expression and function in the impact of psychosocial stress on allergic airway inflammation. 2. Elucidation of the cellular and molecular pathways of the glucocorticoid action on immune cell function and epithelial cell SP-D production in stress-induced exacerbation of the inflammatory airway response.
|Yousefi, Shida; Sharma, Satish K; Stojkov, Darko et al. (2018) Oxidative damage of SP-D abolishes control of eosinophil extracellular DNA trap formation. J Leukoc Biol 104:205-214|
|Sengupta, S; Haczku, A (2017) Targeting I?BNS in allergic asthma: where it resides, matters. Allergy 72:1003-1005|
|Flayer, C H; Haczku, A (2017) The Th2 gene cluster unraveled: role of RHS6. Allergy 72:679-681|
|Killingbeck, S S; Ge, M Q; Haczku, A (2017) Patching it together: epicutaneous vaccination with heat-labile Escherichia coli toxin against birch pollen allergy. Allergy 72:5-8|
|Ge, Moyar Qing; Kokalari, Blerina; Flayer, Cameron H et al. (2016) Cutting Edge: Role of NK Cells and Surfactant Protein D in Dendritic Cell Lymph Node Homing: Effects of Ozone Exposure. J Immunol 196:553-7|
|Yang, Qi; Ge, Moyar Q; Kokalari, Blerina et al. (2016) Group 2 innate lymphoid cells mediate ozone-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol 137:571-8|
|Wang, Yuan; Miwa, Takashi; Ducka-Kokalari, Blerina et al. (2015) Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation. J Immunol 195:1171-81|
|Fang, C L; Yin, L J; Sharma, S et al. (2015) Resistin-like molecule-? (RELM-?) targets airways fibroblasts to effect remodelling in asthma: from mouse to man. Clin Exp Allergy 45:940-952|
|Kim, Won-Keun; Jain, Deepika; Sánchez, Melissa D et al. (2014) Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. Am J Respir Crit Care Med 189:437-48|
|Jordan, Martha; Haczku, Angela (2013) Autoreactive bronchus-associated lymphoid tissue in interstitial lung disease: friend or foe? Am J Respir Cell Mol Biol 48:397-8|
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