Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Abstract

Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H 1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H 3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of bloodbrain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H 3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.blood-brain barrier ͉ experimental allergic encephalomyelitis ͉ multiple sclerosis H istamine [2-(4-imidazole) ethylamine] (HA) is a ubiquitous mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems (1). HA is a potent mediator of inflammation and a regulator of innate and adaptive immunity (2). HA exerts its effect through four G proteincoupled receptors [H 1 , H 2 , H 3 , and H 4 receptor, designated according to the chronological order of their discovery (1)].HA is implicated in the pathophysiology of multiple sclerosis (MS) and its animal models, collectively termed experimental allergic encephalomyelitis (EAE). HA and agents causing the release of HA from mast cells, the primary source of HA in the body (3), alter blood-brain barrier (BBB) permeability. Tissue levels of HA correlate with the onset of EAE (4-6). Inhibitors of mast cell degranulation and H 1 R and H 2 R antagonists modify EAE severity (7)(8)(9)(10)(11)(12). Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15). Moreover, mouse genetic studies have shown that HA, H 1 R, and H 2 R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (16-18). The role of H 3 R and H 4 R in EAE and MS has not been studied.H 3 R is not normally expressed by hematopoietic cells; rather, it is expressed presynaptically where it is an inhibitory autoreceptor (inhibits release of HA from histaminergic neurons) and heteroreceptor (inhibits release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons) (19). Absence of presynaptic inhibition results in failure to limit neurotransmitter rel...

G protein-coupled receptors as therapeutic targets for multiple sclerosis

“…EAE was found to be significantly more severe in these animals [192]. H3R knockout mice also developed a more severe EAE and neuro-inflammation compared with the wild-type animals [193], indicating that the immunosuppressive effect of histamine might be mediated via H3R. However, H1R-deficient mice have been found to be more resistant to EAE induction than wild-type controls [194].…”

Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis

“…In fact, we recently demonstrated that neurogenic control of BBB permeability is negatively regulated by central histamine H 3 receptor signaling. 15 Alterations in BBB permeability can occur in a variety of different situations, 20 some of which relate directly to MS. There is an increasing body of evidence in both EAE 29,30 and MS 31,32 that subtle, progressive alterations in BBB integrity precede the formation of inflammatory lesions.…”

“…Sections from representative areas of the brain and spinal cord were scored in a semiquantitative fashion for the various histopathological parameters as previously described. [15][16][17] Briefly, EAE pathology was scored for the overall severity of the lesions observed, the extent and degree of demyelination and tissue injury (swollen axon sheathes, swollen axons, and reactive gliosis), severity of the acute inflammatory response such as neutrophil infiltration, and the severity of the chronic inflammatory response (lymphocytes/monocytes).…”

Inhibition of Histamine H1 Receptor Activity Modulates Proinflammatory Cytokine Production of Dendritic Cells through c-Rel Activity

“…Each HR is characterized by a specific expression pattern and function. H1R and H2R are ubiquitously expressed on lymphoid and nonlymphoid cells, while H3R [2] and H4R [3,4] are expressed by a majority of cells in the nervous system and on hematopoietic cells, respectively. Histamine primarily mediates acute and chronic allergic inflammation through H1R [5].…”