Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Platelet-monocyte interaction amplifies thromboinflammation through tissue factor signaling in COVID-19.

Abstract

Accumulating evidence into the pathogenesis of COVID-19 highlight a hypercoagulability state with high risk of life-threatening thromboembolic complications. However, the mechanisms of hypercoagulability and their link to hyperinflammation remain poorly understood. Here we investigate functions and mechanisms of platelet activation and platelet-monocyte interactions in inflammatory amplification during SARS-CoV2 infection. We used a combination of immunophenotyping, single cell analysis, functional assays and pharmacological approaches to gain insights on mechanisms. Critically ill COVID-19 patients exhibited increased platelet-monocyte aggregates formation. We identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Single cell RNAseq analysis indicated enhanced fibrinogen receptor Mac-1 in monocytes from severe COVID-19 patients. Monocytes from severe COVID-19 patients displayed increased platelet binding and hyperresponsiveness to P-selectin and fibrinogen with respect to TFN-alpha and IL-1beta secretion. Platelets were able to orchestrate monocyte responses driving TF expression, inflammatory activation and inflammatory cytokines secretion in SARS-CoV-2 infection. Platelet-monocyte interactions ex-vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, while TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially TNF-alpha and IL-1beta. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19.