Cytokines released during infection/inflammation can act on the brain to activate the hypothalamo-pituitary-adrenal (HPA) axis. Glucocorticoid mediators of HPA function serve critical metabolic and immunoregulatory roles that facilitate coping with the immediate threat, and can also impact inflammatory disease processes. Work on this project has defined a model for immune-mediated HPA engagement that involves (1) binding of circulating cytokines by cerebrovascular endothelial cells (ECs), which (2) activate resident macrophages in perivascular spaces (perivascular cells;PVCs) to cyclooxygenase-dependent prostaglandin E2 (PGE2) release. ECs'capacity to display inducible PGE2 synthesis is negatively regulated by PVCs. PGE2 then (3) stimulates brainstem catecholamine neurons that express PGE2 receptors, and, via their axonal projections, (4) hypothalamic neurosecretory neurons that initiate HPA output. We propose to test and refine this model, assess its generality and the potential of manipulating it for intervening in CNS inflammatory disease. First, to test a posited mechanism underlying potent anti-inflammatory influences of PVCs on ECs, via 15-deoxy- ?12,14-prostaglandin J2 (15d-PGJ2) binding by peroxisome proliferator-activated receptor-? (PPAR?), responses of a conditional, EC-specific PPAR? null mouse model to endotoxin challenges will be assessed at each level of the circuit. Transcriptional profiling of PVCs and ECs will be carried out to identify candidate mediators of EC stimulatory influences on PVCs, whose involvement will then be tested. Second, combined axonal transport and histochemical methods will be used to identify sources of endotoxin-sensitive cells that project to hypothalamus and express PGE2 receptors (EP1-4R). Conditional knockout models will assess the role of the EP?R in CNS in general, and in catecholamine neurons specifically, in LPS-induced HPA activation. Third, tract tracing, histochemical and ablation approaches will be used to clarify the hierarchical organization of CNS cell groups that provide for HPA recruitment by insults that differ in nature and intensity. Fourth, we will pursue evidence that variants of the model are operative in engaging CNS/HPA responses to a prototypic emotional stressor, restraint, and an alternate immune challenge presented by bacterial superantigen. Finally, we will test the involvement of the vascular 15d-PGJ2 - PPAR? anti-inflammatory signaling on clinical and neuropathological sequelae of a mouse model of multiple sclerosis, and in the exacerbation of neuropathology in an Alzheimer's Disease model by systemic inflammatory challenges.
Immune-mediated activation of the HPA axis plays important roles in restraining peripheral immune responses, and defending against autoimmunity. In addition, understanding immune signaling across the blood-brain barrier also has implications for the host of neurodegenerative diseases (Alzheimer's, Parkinson's, Prion, ALS) in which CNS inflammatory mechanisms play a contributing role. Elucidation of a potent anti-inflammatory mechanism at the barrier should provide leverage in these and other pathologies.
|Mohammad, Mohammad G; Tsai, Vicky W W; Ruitenberg, Marc J et al. (2014) Immune cell trafficking from the brain maintains CNS immune tolerance. J Clin Invest 124:1228-41|
|Tsai, Vicky Wang-Wei; Manandhar, Rakesh; Jørgensen, Sebastian Beck et al. (2014) The anorectic actions of the TGF? cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One 9:e100370|
|Tsai, Vicky W W; Mohammad, Mohammad G; Tolhurst, Ornella et al. (2011) CCAAT/enhancer binding protein-? expression by dendritic cells regulates CNS autoimmune inflammatory disease. J Neurosci 31:17612-21|
|Garcia-Bueno, Borja; Serrats, Jordi; Sawchenko, Paul E (2009) Cerebrovascular cyclooxygenase-1 expression, regulation, and role in hypothalamic-pituitary-adrenal axis activation by inflammatory stimuli. J Neurosci 29:12970-81|
|Schiltz, Jennifer C; Sawchenko, Paul E (2007) Specificity and generality of the involvement of catecholaminergic afferents in hypothalamic responses to immune insults. J Comp Neurol 502:455-67|
|Brown, David A; Sawchenko, Paul E (2007) Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J Comp Neurol 502:236-60|
|Serrats, Jordi; Sawchenko, Paul E (2006) CNS activational responses to staphylococcal enterotoxin B: T-lymphocyte-dependent immune challenge effects on stress-related circuitry. J Comp Neurol 495:236-54|
|Steiner, Alexandre A; Ivanov, Andrei I; Serrats, Jordi et al. (2006) Cellular and molecular bases of the initiation of fever. PLoS Biol 4:e284|
|Vallieres, Luc; Sawchenko, Paul E (2003) Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci 23:5197-207|
|Reyes, Teresa M; Walker, John R; DeCino, Casey et al. (2003) Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J Neurosci 23:5607-16|
Showing the most recent 10 out of 51 publications