Urocortin Modulates Inflammatory Response and Neurotoxicity Induced by Microglial Activation

Abstract

Microglia are the major inflammatory cells in the brain. Recent studies have highlighted the reciprocal roles of other brain cells in modulating the microglial inflammatory responses. Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. In the present study, we demonstrated that expression of UCN in rat substantia nigra was found to be localized principally to dopaminergic neurons. In cell culture models, the CRH receptors were expressed in microglia, and CRHR expression was up-regulated by treatment with LPS. Thus, it might be proposed that UCN regulates cellular communication between dopaminergic neurons and microglia. We show that femtomolar concentrations of UCN could inhibit LPS-induced TNF-α production in cultured microglia. Investigation of the underlying signaling pathway that mediated the anti-inflammatory effect of UCN the involved PI3K/Akt and glycogen synthase kinase-3β pathway, but not cAMP pathway. Furthermore, UCN protected dopaminergic neurons against LPS-induced neurotoxicity by inhibiting microglial activation in LPS-treated mesencephalic neuron-glia cultures. These results suggest that endogenous UCN and its receptors might be involved in a complex network of paracrine interaction between dopaminergic neurons and glia.

Corticotrophin-releasing hormone (CRH) facilitates axon outgrowth

“…As microglial cells express CRH receptors, 11 BDNF is one of the effector mediators released by microglial cells, 18 we hypothesized that spinal injury-derived CRH might activate microglial cells to release BDNF, which is further involved in neuron axon outgrowth. To prove this hypothesis, using the same rat model mentioned above, we assessed BDNF levels in the spinal cord.…”

“…11 Exogenous CRH can induce microglial cells to release inflammatory mediators and certain neural tissue responses such as inflammation. 10,11 Our results have extended these findings by showing that CRH has the capacity to drive microglial cells to release BDNF in response to spinal cord injury. Apart from inducing the undesired response, such as in stress-related disorders, 24 CRH can modulate behavior by enhancing the behavioral responses to stressors.…”

“…9 Microglial cells express CRH receptor; 10 activation of microglial cells by CRH releases some bioactive molecules, such as BDNF, which are involved in a number of activities of the body. 11 We thus hypothesized that CRH might drive microglial cells to release BDNF; the latter further promotes axon regeneration in neurons. To test this hypothesis, this study aimed to examine (i) the kinetic changes of CRH and BDNF levels in injured spinal cord; (ii) the effect of BDNF on the expression of OMgp in oligodendrocytes; and (iii) whether CRH has the capability to promote axon regeneration.…”

Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis

“…Moreover, in mesencephalic neuron-glia cultures, Ucn inhibited microglial activation and thus protected dopaminergic neurons against LPS-induced neurotoxicity. 43 Further studies in various inflammatory disease settings also suggested that Ucns could have a potential to function as endogenous anti-inflammatory factors. Ucn, a placental peptide, induced secretion of anti-inflammatory cytokines IL-4 and IL-10 from cultured human trophoblast cells isolated from the placentas and reversed LPS-induced TNF- release through the action of CRF 2 receptor.…”

Anti-inflammatory neuropeptides: A new class of endogenous immunoregulatory agents

“…These neuropeptides switch off the inflammatory response by regulating different critical levels of innate immunity (Chorny and Delgado, 2008;Chorny et al, 2008;Delgado et al, 2008a;Gonzalez-Rey et al, 2007a;Miksa et al, 2007;Wang et al, 2007): 1) they inhibit phagocytic activity, free radical production, adherence and migration of macrophages; 2) they reduce production of inflammatory cytokines (TNFα, and various chemokines by activated macrophages and microglia; 3) they downregulate expression of inducible nitric oxide synthase (iNOS) and cycloxygenase 2 (COX2) and the subsequent release of nitric oxide and prostanglandin E2 by macrophages, DCs and microglia; 4) they stimulate production of anti-inflammatory cytokines such as IL-10 and IL-1Ra; 5) they decrease co-stimulatory activity of antigen-presenting cells (APCs) for antigen-specific T cells by downregulating expression of co-stimulatory molecules; 6) they inhibit secretion of late inflammatory mediator highmobility group box 1 (HMGB1); 7) they reduce degranulation of mast cells; 8) they induce apoptosis in macrophages; and 8) they stimulate the peroxisome proliferator-activated receptor-γ (PPARγ), an anti-inflammatory-related transcription factor.…”