Linnerbauer, M. | Search bioRxiv

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (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 factor. We show 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. Selective histamine 3 receptor (H3R) signaling in the intestine is 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 SCFA propionate identified 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2023

Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

immunology↗