Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome.

In an exploratory trial treating "long COVID" with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab. Clinical Trials Registration. NCT04678830.

Gap junctional communication controls the overall endothelial calcium response to vasoactive agonists.

AIMS: A cytosolic calcium (Ca(2+)(i)) increase is an important activation signal for the endothelium. We investigated whether interendothelial spreading of the Ca(2+) signal via gap junctions (GJs) plays a role for the overall Ca(2+)(i) increase in response to vasoactive agonists. METHODS AND RESULTS: In human umbilical vein endothelial cells (HUVECs), a Ca(2+)(i) increase (Fura2) in response to histamine or ATP occurred initially only in about 30% of the cells (initially responding cells) reflecting the cell fraction expressing H(1) or purinergic receptors (FACS/immunohistochemistry). In the remaining adjacent cells, Ca(2+)(i) increases occurred only after a delay of up to 5 s. Blockade of GJ communication (meclofenamic acid and heptanol, or H(2)O(2); verified by dye injection) did not affect responses in the initially responding cells but abolished the delayed Ca(2+)(i) response of the remaining adjacent cells. The resulting reduction in the global endothelial Ca(2+)(i) response significantly reduced the nitric oxide synthesis (assessed as cGMP levels). Similar Ca(2+)(i) results were obtained in the endothelium of freshly isolated mouse (C57BL/6) aortas stimulated with ATP. The receptor-independent Ca(2+)(i) response to ionomycin occurred simultaneously in all cells, regardless of GJ inhibition. In separate experiments, inhibition of the IP(3) receptor (xestospongin-C; 40, µmol/L) but not of the ryanodine receptor (ryanodine, 250 µmol/L) reduced the spread of the Ca(2+)(i) signal into adjacent cells over longer distances. CONCLUSION: The global Ca(2+)(i) response of the endothelium to agonists is determined decisively by the functionality of GJs, thus establishing a new role for GJs in controlling endothelial activity and vasomotor function.