Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
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Research Article Autoimmunity Immunology

Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation

Abstract

Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota–derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist–induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.

Authors

Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss

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Figure 2

Resolution depends on intestinal histamine and H3R signaling.

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Resolution depends on intestinal histamine and H3R signaling. (A) Clinic...
(A) Clinical arthritis score shown as paw thickness (mm) of CIA mice ± histamine (n = 12–14) at the peak of disease. (B) Area of inflammation expressed as absolute mm2 per analyzed H&E-stained paw sections of CIA mice ± histamine (n = 5) and example histology images. Scale bars: 500 μm. (C) Serum levels of RANTES/CCL5 and MCP-1/CCL2. (D) PCoA plot of 16s rRNA-Seq of CIA mice ± histamine. Permutational multivariate analysis of variance (ADONIS) was significant (R2 = 0.18944, P = 0.0437). (E) Relative abundance of the bacterial families identified by 16s rRNA-Seq. (F) Relative abundance of most changed Lactobacillaceae strains after histamine treatment. (G) Clinical arthritis score shown as paw thickness (mm) of CIA mice after transfer of PBS (control), E. coli, or HDC positive E. coli at the peak of disease (n = 4–5). (H) Clinical arthritis score shown as paw thickness (mm) of CIA mice after oral transfer of histamine or specific agonists for H1R–H4R. (n = 4–5). (I) t-SNE plot of spectral flow cytometric analysis of the spleen from CIA mice plus H3R agonist RαMH. (J) CD4+ T cells in the synovium. (K) RORγt+ CD4+ T cells in the synovium. (L) RORγt+ CD4+ T cells in the pLN. (M) Neutrophils in the pLN. (N) CD8+ T cells in the pLN. Data are expressed as mean ± SD. Statistical difference was determined by Student’s t test (B, C, and J–N), t test or 1-way ANOVA of AUC (A, G, and H), and ADONIS (D). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. CIA, collagen-induced arthritis; pLN, popliteal lymph node; PCoA, principal coordinates analysis.