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

Abstract

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...

G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

“…S1P regulates barrier function, and mice deficient in S1P in plasma were more susceptible to HA-induced vascular leakage (61). Nonetheless, administration of PTX to mice expressing EC-specific H 1 R did not render them sensitive to VAASH (16), which argues against this notion. Taken together, these results did not formally rule out the possibility that Hrh1 on EC is required but suggested that coexpression of H 1 R in another component of the vascular unit may be required for Bphs.…”

“…Using bone marrow chimeras, we found that the nonhematopoietic compartment determined susceptibility to Bphs (16). We found that EC-specific expression of H 1 R was not sufficient to mediate Bphs (16).…”

“…In this regard, PTX has long been known to alter vascular permeability through its ability to promote VAAS (53). The vasoactive amines HA, 5-HT, and BDK have all been shown to influence vascular permeability, in particular, the BBB (16,53,54). Here we have shown that after PTX sensitization, (i) hypersensitivity to HA, 5-HT, or BDK (Bphs, Bpss, and Bpbs, respectively) is uniquely genetically controlled; (ii) unlike the genetic control of Bphs, that of Bpss and Bpbs and is not linked to any of the known 5-HT or BDK receptors; (iii) Bpbs is mediated by Bdkrb2; and (iv) G␣ i1/3 proteins are the physiological in vivo targets of ADP-ribosylation by PTX associated with VAASH.…”

“…A T cell-specific role for H 1 R in disease susceptibility was found (15), but a bone marrow chimeric approach revealed that expression of H 1 R in the nonhematopoietic compartment was responsible for Bphs (16), prompting the closer look at the mechanism of Bphs that we took in this study.…”

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

“…Although the BBB is primarily formed by the endothelium of cerebral capillaries, there are specific interactions and communication at the abluminal side of the BBB with the other cell components of the neurovascular unit (NVU): pericytes, astrocytes, and neurons (Abbott et al, 2010). The local regulation of mediators like neurotransmitters and their movement across these blood-nerve barriers has received relatively little attention, despite the fact that this could influence and terminate receptor-mediated effects on, at least, the integrity and permeability of the brain capillaries of the NVUs (Leybaert, 2005;Lu et al, 2010).…”