Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

Abstract

Histamine H3 receptor (Hrh3/H3R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H3R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H3R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H3RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H3R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H3R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury

“…The neurotherapeutic effects of GSK247246 against PWMI are also supported by positive effects of another H3R antagonist/inverse agonist GSK239512 on lesion remyelination in a small cohort of human relapsing-remitting multiple sclerosis patients (Schwartzbach et al, 2017). Modulation of the neuroinflammatory responses are considered to be the chief therapeutic effects of H3R modulation either by direct effects on innate or adaptive immune cells (Ferreira et al, 2012;Saligrama et al, 2013;Saligrama et al, 2012;Teuscher et al, 2007) discussed further below, or via effects on pathways innervating immune tissues (Krementsov et al, 2013). Nevertheless, direct effects on oligodendrocytes also cannot be excluded in this study.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The reasons for this heterogeneity are complex and still not fully understood. H 3 receptor isoforms have been identified in the rat (Drutel et al, 2001;Morisset et al, 2001), mouse (Rouleau et al, 2004;Krementsov et al, 2013), and guinea pig (TardivelLacombe et al, 2000).…”

“…By comparing EAEsusceptible and -resistant mice strains as well as H 3 receptor KO mice, a functional link between central H 3 receptor signaling and peripheral immune responses was proposed (Krementsov et al, 2013).…”

Ergoline‐Derived Inverse Agonists of the Human H3 Receptor for the Treatment of Narcolepsy

“…Coupling constants (J) are reported in Hertz (Hz). Liquid chromatography/mass spectrometry (LC/MS) analyses were run on an Agilent 1200 HPLC/6110 SQ system; mobile phase: 10 mm aq NH 4 …”

“…[2] H3R inverse agonists have been proposed as agents for the treatment of numerous maladies, [3] ranging from cardiovascular, inflammatory, respiratory and pain disorders to migraine, attention deficit hyperactivity disorder (ADHD), as well as multiple sclerosis [4] and Tourette's syndrome. [5] A particular focus of research has been on the development of H3R inverse agonists for the management of sleep disorders such as narcolepsy.…”