Substance P receptor mediated maintenance of chronic inflammation in EAE

Reinke, Emily K.; Johnson, Matthew; Ling, Changying; Karman, Jozsef; Lee, Jang Eun; Weinstock, Joel V.; Sándor, Mátyás; Fábry, Zsuzsa

doi:10.1016/j.jneuroim.2006.07.010

Cited by 34 publications

(33 citation statements)

References 48 publications

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“…The present findings are consistent with previous studies showing that SP/NK-1R interactions are required for the maintenance of chronic EAE-associated inflammation (32). In addition, SP antagonists have been found to reduce in vivo CNS inflammation elicited by Trypanosoma brucei (33) and attenuate astrocyte activation in a murine model of post-treatment reactive encephalopathy that mimics late stage diminazene-treated African Trypanosomiasis (34).…”

Section: Discussionsupporting

confidence: 93%

Neurogenic Exacerbation of Microglial and Astrocyte Responses toNeisseria meningitidisandBorrelia burgdorferi

Chauhan

Sterka

Gray

et al. 2008

The Journal of Immunology

109

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Although glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident CNS cells to initiate and/or augment inflammation following trauma or infection. The tachykinin, substance P (SP), is well known to augment inflammatory responses at peripheral sites and its presence throughout the CNS raises the possibility that this neuropeptide might serve a similar function within the brain. In support of this hypothesis, we have recently demonstrated the expression of high affinity receptors for SP (Neurokinin-1 (NK-1) receptors) on microglia and shown that this tachykinin can significantly elevate bacterially induced inflammatory prostanoid production by isolated cultures of these cells. In the present study, we demonstrate that endogenous SP/NK-1R interactions are an essential component in the initiation and/or progression of CNS inflammation in vivo following exposure to two clinically relevant bacterial CNS pathogens, Neisseria meningitidis and Borrelia burgdorferi. We show that in vivo elevations in inflammatory cytokine production and decreases in the production of an immunosuppressive cytokine are markedly attenuated in mice genetically deficient in the expression of the NK-1R or in mice treated with a specific NK-1R antagonist. Furthermore, we have used isolated cultures of microglia and astrocytes to demonstrate that SP can augment inflammatory cytokine production by these resident CNS cell types following exposure to either of these bacterial pathogens. Taken together, these studies indicate a potentially important role for neurogenic exacerbation of resident glial immune responses in CNS inflammatory diseases, such as bacterial meningitis.

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Section: Discussionsupporting

confidence: 93%

Neurogenic Exacerbation of Microglial and Astrocyte Responses toNeisseria meningitidisandBorrelia burgdorferi

Chauhan

Sterka

Gray

et al. 2008

The Journal of Immunology

109

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“…This EAE model features inflammation of complex pathogenesis, demyelination, which is the hallmark of MS, axonal loss or damage, and gliosis 34 . Studies confirmed that SP-mediated signaling contributes to the maintenance of inflammation in the CNS during the chronic phase of EAE 35 and likely stimulates Th1 and Th17 autoreactive cells. These migrate to the CNS, enhance BBB crossing, and perpetuate inflammation 19 .…”

Section: Neuroinflammation and Substance Pmentioning

confidence: 77%

“…Studies in the MS murine model EAE show evidence that SP-mediated signaling contributes to the maintenance of inflammation in the CNS during the chronic phase of the disease. Consequently, the genetic absence of NK1R or its suppression using the synthetic antagonist SR140333 showed beneficial effects in the chronic stages of the disease, but not during the acute phase 35 . Similarly, in a different study using the EAE model, the authors evaluated the effect of CP-96,345, a selective NK1R antagonist, and found marked suppression of clinical and histological signs of EAE after early treatment, although severity could not be modulated if treatment was started at the peak of disease 67 .…”

Section: Nk1r Antagonists and Neurodegenerative Diseasesmentioning

confidence: 99%

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Martínez

Philipp

2016

J Neurol Neuromedicine

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This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.

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“…In a posttreatment-reactive encephalopathy model of Trypanosoma brucei, NK1R-deficient mice have a significantly reduced clinical impairment, but a more severe neuroinflammatory response, compared with wild-type mice (41). The critical roles of SP were reported in T cell-mediated experimental autoimmune encephalomyelitis models (42,43). The findings strongly suggest that the SP-NK1R-signaling cascade contributes to type 1 immunity, as well as inflammatory responses.…”

Section: Discussionmentioning

confidence: 89%

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

Kitamura

Kobayashi

Wakita

et al. 2012

The Journal of Immunology

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Neurokinin A (NKA), a neurotransmitter distributed in the central and peripheral nervous system, strictly controls vital responses, such as airway contraction, by intracellular signaling through neurokinin-2 receptor (NK2R). However, the function of NKA–NK2R signaling on involvement in immune responses is less-well defined. We demonstrate that NK2R-mediated neuropeptide signaling activates dendritic cell (DC)-mediated type 1 immune responses. IFN-γ stimulation significantly induced NK2R mRNA and remarkably enhanced surface protein expression levels of bone marrow-derived DCs. In addition, the DC-mediated NKA production level was significantly elevated after IFN-γ stimulation in vivo and in vitro. We found that NKA treatment induced type 1 IFN mRNA expressions in DCs. Transduction of NK2R into DCs augmented the expression level of surface MHC class II and promoted Ag-specific IL-2 production by CD4+ T cells after NKA stimulation. Furthermore, blockade of NK2R by an antagonist significantly suppressed IFN-γ production by both CD4+ T and CD8+ T cells stimulated with the Ag-loaded DCs. Finally, we confirmed that stimulation with IFN-γ or TLR3 ligand (polyinosinic-polycytidylic acid) significantly induced both NK2R mRNA and surface protein expression of human PBMC-derived DCs, as well as enhanced human TAC1 mRNA, which encodes NKA and Substance P. Thus, these findings indicate that NK2R-dependent neuropeptide signaling regulates Ag-specific T cell responses via activation of DC function, suggesting that the NKA–NK2R cascade would be a promising target in chronic inflammation caused by excessive type 1-dominant immunity.

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Substance P receptor mediated maintenance of chronic inflammation in EAE

Cited by 34 publications

References 48 publications

Neurogenic Exacerbation of Microglial and Astrocyte Responses toNeisseria meningitidisandBorrelia burgdorferi

Neurogenic Exacerbation of Microglial and Astrocyte Responses toNeisseria meningitidisandBorrelia burgdorferi

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

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