Dataset Information

A succinate/SUCNR1-brush cell defense program in the tracheal epithelium.

ABSTRACT: Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a signaling cascade involving the succinate receptor 1 (SUCNR1), phospholipase Cβ2, and the cation channel transient receptor potential channel subfamily M member 5 (TRPM5). Stimulated brush cells then trigger a long-range Ca²⁺ wave spreading radially over the tracheal epithelium through a sequential signaling process. First, brush cells release acetylcholine, which excites nearby cells via muscarinic acetylcholine receptors. From there, the Ca²⁺ wave propagates through gap junction signaling, reaching also distant ciliated and secretory cells. These effector cells translate activation into enhanced ciliary activity and Cl^- secretion, which are synergistic in boosting mucociliary clearance, the major innate defense mechanism of the airways. Our data establish tracheal brush cells as a central hub in triggering a global epithelial defense program in response to a danger-associated metabolite.

SUBMITTER: Perniss A

PROVIDER: S-EPMC10396310 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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A succinate/SUCNR1-brush cell defense program in the tracheal epithelium.

Perniss Alexander A Boonen Brett B Tonack Sarah S Thiel Moritz M Poharkar Krupali K Alnouri Mohamad Wessam MW Keshavarz Maryam M Papadakis Tamara T Wiegand Silke S Pfeil Uwe U Richter Katrin K Althaus Mike M Oberwinkler Johannes J Schütz Burkhard B Boehm Ulrich U Offermanns Stefan S Leinders-Zufall Trese T Zufall Frank F Kummer Wolfgang W

Science advances 20230802 31

Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a signaling cascade involving the succinate receptor 1 (SUCNR1), phospholipase Cβ2, and the cation channel transient receptor potential channel subfamily M member 5 (TRPM5). Stimulated brush cells then trigger a long-range Ca<sup>2+</sup> wave spreading radially over the tracheal epithelium through a sequential signaling process. ...[more]

PMID: 37531421

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Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. Succinate is an inflammatory metabolic signal that exacerbates RA synovitis by activating succinate receptor 1 (SUCNR1) to amplify the release of IL-1β. Thus, inhibition of succinate activation of SUCRN1 could be an effective method to inhibit the inflammation of RA. Baihu Jia Guizhi decoction (BHGZ), which is composed of Gypsum Fibrosum, Anemarrhena asphodeloides Bge., Cinnamomum cassia Presl., Glycyrrhiza uralensis Fisch., and Oryza sativa L., is a Traditional Chinese Medicine (TCM) prescription used to treat RA in clinic. In addition, TCM believes that damp and heat environment is one of the causes of RA. In this study, we tested the role of damp and heat environments in exacerbating RA inflammation and the anti-inflammatory effect of BHGZ, based on succinate/SUCNR1/IL-1β pathway in the adjuvant arthritis (AA) model with damp and heat environment (AA + DHE). Results showed that paw swelling and synovial pathology were significantly increased in AA rats, and these results were aggravated by stimulation in damp and heat environment. BHGZ improved AA + DHE rats' paw swelling, synovial hyperplasia, and inflammatory cell infiltration and reduced IL-1β. In addition, AA rats significantly increased the expression of SUCNR1, and the stimulation of damp and heat environment not only increased the expression of SUCNR1 but also promoted the accumulation of succinate. BHGZ simultaneously reduced the concentration of succinate and the expression of SUCNR1. Finally, SDH activity was decreased in AA rats and AA + DHE rats, while BHGZ increased SDH activity and then reduced succinate concentration. Therefore, we prove that damp and heat environment deteriorated the inflammation of RA which is the activation of succinate/SUCNR1 pathway, while BHGZ regulates SDH activity to reduce the accumulation of succinate and inhibit the activation of SUCNR1 that is the underlying mechanism of its treatment of RA.

Dataset Information

A succinate/SUCNR1-brush cell defense program in the tracheal epithelium.

Publications

A succinate/SUCNR1-brush cell defense program in the tracheal epithelium.

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