Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Noubade, Rajkumar; Milligan, Graeme; Zachary, James F.; Blankenhorn, Elizabeth P.; Rio, Roxana del; Rincón, Mercedes; Teuscher, Cory

doi:10.1172/jci32792

Cited by 76 publications

(122 citation statements)

References 66 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…Age-matched cohorts of WT, H 1 RKO, and H 1 RKO-vWF H1R Tg mice were immunized with MOG 35-55 + complete Freund's adjuvant (CFA) + PTX, and clinical scores over a 30-d period were recorded. As expected (21,22), H 1 RKO mice developed less severe disease than WT mice (Fig. 3A).…”

Section: Resultssupporting

confidence: 83%

“…We have previously reported decreased EAE susceptibility in H 1 R-deficient mice (21) and that expression of H 1 R in T cells complements EAE in H 1 RKO mice (22). In contrast, in this study, we show that overexpression of H 1 R on endothelial cells further suppressed the residual disease symptoms present in H 1 RKO mice.…”

Section: Discussioncontrasting

confidence: 85%

“…However, compared with WT mice, both H 1 RKO and H 1 RKO-vWF H1R Tg T cells produced less IFN-γ in response to MOG in vitro. We believe that the reduced encephalitogenicity of T cells in H 1 RKO and H 1 RKO-vWF H1R Tg mice likely reflects a T-cell-inherent defect, presumably attributable to the requirement for H 1 R for the full encephalitogenic capacity of T cells (22) rather than an effect on endothelial cells.…”

Section: Discussionmentioning

confidence: 92%

“…H 1 RKO-vWF H1R Tg mice were generated by injection of a DNA fragment containing the murine Vwf promoter (24), the HA-tagged Bphs S Hrh1 allele (22), and the human growth hormone (hGH) intron/polyadenylation signal directly into fertilized C57BL/6J eggs at the University of Vermont Transgenic/Knockout Mouse Facility. Transgene-positive founders were identified by DNA slot-blot using a BamHI-SacI 0.5-kb fragment from the hGH gene as a probe.…”

Section: Methodsmentioning

confidence: 99%

“…Expression of H 1 R on T cells is required for their full encephalitogenic potential (22), but the contribution of H 1 R signaling in other cell types to the pathogenesis of EAE has not been formally addressed. In this study, we focused on endothelial cells because they express H 1 R, play a role in both Bphs and EAE, and are important in controlling vascular permeability.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Lu¹,

Diehl²,

Noubade³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) T he blood-brain barrier (BBB) involves endothelial cells that line the blood vessels of the central nervous system (CNS) and the tight junction protein complexes between these endothelial cells. The BBB thereby acts as a physical and metabolic barrier by separating the vasculature from the parenchyma of the CNS (1). Breakdown of the BBB is associated with the onset and pathogenesis of multiple sclerosis (MS), a degenerative, demyelinating, inflammatory disease of the CNS (2). In MS and its autoimmune model, experimental autoimmune encephalomyelitis (EAE), activated T cells cross the BBB into the perivascular space of the CNS, causing damage to neurons (2). Surveillance of the CNS by T cells does occur (3), but the paucity of leukocytes found in the CNS under noninflammatory conditions suggests that extravasation of cells across the BBB is tightly regulated. Therefore, identifying factors that modulate BBB permeability may be of therapeutical value in treating inflammatory demyelinating diseases of the CNS.Bordetella pertussis-induced hypersensitivity to histamine (Bphs/ Bphs) is a genetically controlled intermediate phenotype associated with susceptibility to EAE (4). Bphs is a state wherein mice are rendered highly susceptible to histamine after a preceding injection of B. pertussis toxin (PTX) (5). Bphs-susceptible strains of mice die within 30 min after histamine challenge, presumably attributable to hypotensive and hypovolemic shock. The cells targeted during Bphs are not known. Histamine has also been implicated in the pathophysiology of MS and EAE. Increased tissue levels of histamine correlate with the onset of EAE (6-8). Mast cells, the major source of histamine (9), are present in MS lesions (10-12), and evidence of mast cell activation is found in the cerebrospinal fluid (CSF) of patients who have MS (13). In mice, mast cells (14) and their activation (15) are required for early EAE onset and maximal disease severity.The effects of histamine are mediated by four surface histamine receptors: H 1 R, H 2 R, H 3 R, and H 4 R (16). H 1 R protein and mRNA are highly expressed in MS lesions (17), and H 1 antihistamines reduce EAE in mice and rats (17,18). In patients with MS, the use of sedating H 1 antihistamines is correlated with decreased disease incidence and amelioration of symptoms (19,20). Our laboratory has shown that susceptibility to Bphs and EAE requires expression of Hrh1, the gene encoding H 1 R (21).Expression of H 1 R on T cells is required for their full encephalitogenic potential (22), but the contribution of H 1 R signaling in other cell types to the pathogenesis of EAE has not been formally addressed. In this study, w...

show abstract

Section: Resultssupporting

confidence: 83%

Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Lu¹,

Diehl²,

Noubade³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

Sex‐specific control of central nervous system autoimmunity by p38 mitogen‐activated protein kinase signaling in myeloid cells

Krementsov

Noubade

Dragon

et al. 2014

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

Objective-Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsingremitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored.Methods-Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses.Results-Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female-and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females.Interpretation-Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS.

show abstract

Combinatorial roles for histamine H₁‐H₂ and H₃‐H₄ receptors in autoimmune inflammatory disease of the central nervous system

et al. 2012

Self Cite

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H1–H4. We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H1R and H2R are propathogenic, while H3R and H4R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H1H2RKO and H3H4RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H1H2RKO mice developed a less severe clinical disease course, whereas the disease course of H3H4RKO mice was more severe. H1H2RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H3H4RKO mice. Additionally, splenocytes from immunized H1H2RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.

show abstract

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Cited by 76 publications

References 66 publications

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Sex‐specific control of central nervous system autoimmunity by p38 mitogen‐activated protein kinase signaling in myeloid cells

Combinatorial roles for histamine H₁‐H₂ and H₃‐H₄ receptors in autoimmune inflammatory disease of the central nervous system

Contact Info

Product

Resources

About

Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice

Cited by 76 publications

References 66 publications

Endothelial histamine H 1 receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H 1 receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Sex‐specific control of central nervous system autoimmunity by p38 mitogen‐activated protein kinase signaling in myeloid cells

Combinatorial roles for histamine H1‐H2 and H3‐H4 receptors in autoimmune inflammatory disease of the central nervous system

Contact Info

Product

Resources

About

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Combinatorial roles for histamine H₁‐H₂ and H₃‐H₄ receptors in autoimmune inflammatory disease of the central nervous system