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

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(2+) 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 Ca(2+) 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.

• Perniss, A.
• Boonen, B.
• Tonack, S.
• Thiel, M.
• Poharkar, K.
• Alnouri, M. W.
• Keshavarz, M.
• Papadakis, T.
• Wiegand, S.
• Pfeil, U.
• Richter, K.
• Althaus, M.
• Oberwinkler, J.
• Schütz, B.
• Boehm, U.
• Offermanns, S.
• Leinders-Zufall, T.
• Zufall, F.
• Kummer, W.