title: Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.
abstract: Histamine H(3) receptor (Hrh3/H(3)R) 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 H(3)R-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 H(3)R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3)RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3)R 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 H(3)R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont, USA.
authors.forename: Dimitry N
authors.initials: DN
authors.lastname: Krementsov
authors.forename: Emma H
authors.initials: EH
authors.lastname: Wall
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Martin
authors.forename: Meenakumari
authors.initials: M
authors.lastname: Subramanian
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Noubade
authors.forename: Roxana
authors.initials: R
authors.lastname: Del Rio
authors.forename: Gary M
authors.initials: GM
authors.lastname: Mawe
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*
chemical_list: D020033:Protein Isoforms; D018100:Receptors, Histamine H3
references.citation: Nat Immunol. 2007 Sep;8(9):992-1000
references.pmid: 17660822
references.citation: J Immunol. 1985 Aug;135(2 Suppl):755s-765s
references.pmid: 2861231
references.citation: J Clin Invest. 2002 Dec;110(12):1791-9
references.pmid: 12488429
references.citation: Pain. 2004 Aug;110(3):560-570
references.pmid: 15288396
references.citation: Nat Rev Neurol. 2010 Aug;6(8):455-61
references.pmid: 20606678
references.citation: J Immunol. 1983 Oct;131(4):1714-27
references.pmid: 6619542
references.citation: Eur J Pharmacol. 1994 May 17;267(3):343-8
references.pmid: 8088374
references.citation: J Neuroinflammation. 2012 Jun 29;9:150
references.pmid: 22747709
references.citation: Ann Neurol. 2009 Mar;65(3):239-48
references.pmid: 19334069
references.citation: Nature. 2007 Nov 1;450(7166):110-4
references.pmid: 17934446
references.citation: Gastroenterology. 2012 Apr;142(4):844-854.e4
references.pmid: 22226658
references.citation: Sci Transl Med. 2012 Aug 1;4(145):145ra105
references.pmid: 22855462
references.citation: Pain. 2008 Jun;136(3):293-304
references.pmid: 17766043
references.citation: Scand J Immunol. 1980;12(5):433-41
references.pmid: 7466330
references.citation: J Clin Invest. 2007 Nov;117(11):3507-18
references.pmid: 17965772
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9970-5
references.pmid: 16777955
references.citation: Nat Immunol. 2004 Jun;5(6):575-81
references.pmid: 15164017
references.citation: Acta Neuropathol. 2011 Aug;122(2):155-70
references.pmid: 21626034
references.citation: J Exp Med. 2012 Jun 4;209(6):1057-68
references.pmid: 22665702
references.citation: Med Clin North Am. 2009 Mar;93(2):451-76, ix-x
references.pmid: 19272518
references.citation: Brain Behav Immun. 2007 Aug;21(6):736-45
references.pmid: 17467231
references.citation: J Neurosci Res. 2008 Sep;86(12):2624-40
references.pmid: 18500752
references.citation: Science. 2002 Jul 26;297(5581):620-3
references.pmid: 12142541
references.citation: Eur J Pharmacol. 2003 Apr 25;467(1-3):57-65
references.pmid: 12706455
references.citation: Expert Opin Investig Drugs. 2005 Mar;14(3):223-41
references.pmid: 15833055
references.citation: Neurol Sci. 2010 Nov;31(Suppl 2):S255-9
references.pmid: 20635112
references.citation: Immunity. 2007 Jul;27(1):160-71
references.pmid: 17658276
references.citation: Nat Rev Neurol. 2011 Aug 16;7(9):519-27
references.pmid: 21844896
references.citation: NeuroRehabilitation. 2011;29(3):197-219
references.pmid: 22142753
references.citation: Eur J Pharmacol. 2008 Jun 10;587(1-3):336-8
references.pmid: 18439995
references.citation: Neurology. 2009 May 12;72(19):1693-701
references.pmid: 19433744
references.citation: Thorax. 1983 May;38(5):333-40
references.pmid: 6348994
references.citation: J Clin Invest. 2003 Jan;111(2):241-50
references.pmid: 12531880
references.citation: Science. 2006 Jun 16;312(5780):1669-72
references.pmid: 16709748
references.citation: Nat Med. 2003 Mar;9(3):287-93
references.pmid: 12598893
references.citation: Annu Rev Neurosci. 1999;22:443-85
references.pmid: 10202545
references.citation: Neurol Res. 2006 Apr;28(3):230-5
references.pmid: 16687046
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Nat Immunol. 2009 Jul;10(7):786-93
references.pmid: 19503106
references.citation: Eur J Pharmacol. 1992 Jan 7;210(1):31-5
references.pmid: 1318202
references.citation: Biochem J. 2001 Apr 15;355(Pt 2):279-88
references.pmid: 11284713
references.citation: Curr Opin Neurol. 2005 Jun;18(3):225-30
references.pmid: 15891404
references.citation: PLoS One. 2009 Jun 23;4(6):e6004
references.pmid: 19547708
references.citation: J Immunol. 1998 Aug 15;161(4):1860-7
references.pmid: 9712054
references.citation: Lancet Neurol. 2008 Mar;7(3):268-77
references.pmid: 18275928
references.citation: Mol Pharmacol. 1999 Jun;55(6):1101-7
references.pmid: 10347254
references.citation: Acta Neuropathol. 2012 May;123(5):627-38
references.pmid: 22327362
references.citation: Brain Res. 2006 Nov 20;1120(1):172-82
references.pmid: 17007822
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: J Biol Chem. 2009 Apr 24;284(17):11152-9
references.pmid: 19258313
references.citation: Lancet Neurol. 2004 Feb;3(2):104-10
references.pmid: 14747002
references.citation: Neuropathol Appl Neurobiol. 2011 Dec;37(7):698-710
references.pmid: 21696413
references.citation: Neuron. 2009 Oct 15;64(1):28-32
references.pmid: 19840545
references.citation: PLoS Negl Trop Dis. 2011 Jun;5(6):e1178
references.pmid: 21666794
references.citation: Mol Pharmacol. 2006 Apr;69(4):1194-206
references.pmid: 16415177
references.citation: J Neuroimmunol. 2008 Sep 15;201-202:183-99
references.pmid: 18632165
references.citation: Nat Rev Neurol. 2011 May 10;7(6):332-42
references.pmid: 21556031
references.citation: J Biol Chem. 2003 Dec 12;278(50):50754-64
references.pmid: 14522968
references.citation: J Immunol. 1999 Mar 1;162(5):3096-102
references.pmid: 10072563
references.citation: Int Immunol. 2001 Mar;13(3):257-64
references.pmid: 11222494
references.citation: Blood. 2005 Sep 1;106(5):1843-50
references.pmid: 15886329
references.citation: Nat Immunol. 2008 Feb;9(2):155-65
references.pmid: 18193049
references.citation: Curr Opin Neurol. 2001 Jun;14(3):279-87
references.pmid: 11371749
references.citation: Brain Behav Immun. 2009 May;23(4):507-17
references.pmid: 19486646
references.citation: Arch Med Res. 2011 Jan;42(1):44-7
references.pmid: 21376262
references.citation: Lab Invest. 1999 Oct;79(10):1181-99
references.pmid: 10532583
references.citation: J Pharmacol Exp Ther. 2007 Dec;323(3):888-98
references.pmid: 17855474
references.citation: Curr Top Med Chem. 2011;11(6):648-60
references.pmid: 21261594
references.citation: Immunity. 2009 Aug 21;31(2):342-55
references.pmid: 19699173
references.citation: Inflamm Res. 2004 Oct;53(10):509-16
references.pmid: 15597144
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: J Neural Transm (Vienna). 2002 Apr;109(4):443-53
references.pmid: 11956964
references.citation: Trends Neurosci. 2008 Dec;31(12):645-52
references.pmid: 18952304
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10146-51
references.pmid: 17548817
references.citation: Mult Scler. 2009 Jul;15(7):779-88
references.pmid: 19542262
references.citation: Pain. 2009 Jan;141(1-2):156-64
references.pmid: 19084337
references.citation: Mol Pharmacol. 2002 Aug;62(2):389-97
references.pmid: 12130692
references.citation: Neuropharmacology. 2002 Jun;42(7):929-40
references.pmid: 12069903
references.citation: Mol Pharmacol. 2001 Jan;59(1):1-8
references.pmid: 11125017
references.citation: J Immunol. 2008 Jun 1;180(11):7471-9
references.pmid: 18490747
references.citation: Nat Rev Immunol. 2009 Jun;9(6):418-28
references.pmid: 19461672