Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)
Goretzko, J.; Heitzig, N.; Thomas, K.; Krogsaeter, E. K.; Nass, J.; Linard Matos, A. L.; Wegner, T.; Schloer, S.; Gerke, V.; Rossaint, J.; Glorius, F.; Bracher, F.; Grimm, C. M.; Rescher, U.
Show abstract
In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leukocyte receptor P-selectin together with the stabilizing co-factor CD63. We found that diminished expression of the endolysosomal non-selective cation channel TPC2 or inhibition of TPC2-mediated Ca2+-release via trans-Ned 19 led to reduced endolysosomal Ca2+ efflux, and blocked transfer of CD63 from late endosomes/lysosomes (LEL) to WPB, and a concomitant loss of P-selectin on the endothelial cell surface. Accordingly, P-selectin-mediated leukocyte recruitment to trans-Ned 19-treated HUVEC under flow was significantly reduced without disturbing VWF exocytosis. Our findings establish the endolysosome-related TPC2 Ca2+ channel as a key element in the maintenance of proper endothelial functions and a potential pharmacological target in the control of inflammatory leukocyte recruitment.
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