Microbiota-derived histamine promotes resolution of synovial inflammation via the central nervous system
DÜRHOLZ K. 1,2, SCHMID E. 1,2, DANZER H. 1,2, FRECH M. 1,2, LINNERBAUER M. 3, LÖßLEIN L. 3, SCHÄLTER F. 1,2, LUCAS S. 1,2, AZIZOV V. 1,2, HOFMANN J. 4, ILJAZOVIC A. 5, STROWIG T. 5, TAUDTE R. 6, FROMM M. 6, XIANG W. 7, AKDIS C. 8, ROTHHAMMER V. 3, SCHETT G. 1,2, ZAISS M. 1,2
1 Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany, Erlangen, Germany; 2 Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany, Erlangen, Germany; 3 Department of Neurology, University Hospital Erlangen, Friedrich–Alexander University Erlangen–Nürnberg, Erlangen, Germany, Erlangen, Germany; 4 Department of Biology, Division of Biochemistry, Friedrich-Alexander University (FAU), Erlangen, Germany , Erlangen, Germany; 5 Helmholtz Centre for Infection Research, Braunschweig, Germany, Erlangen, Germany; 6 Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany, , Erlanen, Germany; 7 Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität, Erlangen-Nürnberg (FAU), Erlangen, Germany, , Erlangen, Germany; 8 Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland, Davos, Switzerland
Rheumatoid arthritis (RA) is a highly prevalent chronic inflammatory disease. The intestinal microbiota produces metabolites with immunomodulatory functions, like short-chain fatty acids (SCFA), but also neuroactive substances like histamine. Histamine is mainly known for its role in allergic reactions. Aside from this effect histamine can have immunoregulatory functions. Here, we aimed to unravel the effect of microbiota derived histamine on peripheral inflammation.
Mice with collagen-induced arthritis (CIA) were treated orally with histamine-producing and control E. Coli. from peak of disease (POD). Mice were treated orally with histamine or histamine-receptor agonists (H1RA-H4RA). To identify the route of action we treated our mice orally, intraperitoneally and intrathecally with a H3RA. Serum and spinal cord extracts of H3RA-treated and untreated CIA mice were analyzed by untargeted metabolomics. Spinal cord and the paw innervating nervus plantaris were analyzed by bulk RNA sequencing and cytek spectral flow cytometry.
We identified histamine as increased metabolite upon oral treatment with the SCFA propionate. Transfer of histamine-producing bacteria to mice with CIA at POD severity significantly accellerated resolution of inflammation. Oral, but not i.p. or i.th. treatment with histamine from POD induced significant improvement of clinical symptoms, mediated through H3R activation. H3R is mainly expressed on cells of the nervous system. Analysis of the spinal cords of H3RA-treated vs untreated CIA mice showed lower expression of c-FOX and p-p38, both are associated with higher disease activity. CIA mice showed higher levels of inflammatory microglia in the spinal cord compared to healthy controls, H3RA-treated mice showed a normal balance of homeostatic to inflammatory microglia. Untargeted metabolomics and RNAseq furthermore revealed significant changes in the metabolite and transcription profile in CNS and PNS.
In summary, we show that microbiota-derived histamine induces resolution of ongoing inflammation in mice with CIA, mediated through the H3R and via the central nervous system.