Platelet activation and platelet-monocyte interaction amplify thromboinflammation in obesity through adhesion molecules and endothelial IL-1R signaling.

BACKGROUND

Obesity is a global health concern associated with chronic low-grade inflammation that supports high cardiometabolic risk. Proinflammatory and prothrombotic states contribute to the development of cardiovascular diseases, a leading cause of mortality in obesity. Platelets are chief effectors of hemostasis and pathologic thrombosis that have been highlighted for their key roles in inflammation and immunity. Platelets secrete inflammatory mediators and interact with leukocytes, regulating crucial responses. However, the mechanisms and functional responses of platelet-leukocyte aggregates in obesity and their link to chronic low-grade inflammation remain elusive.

OBJECTIVES

We aimed to investigate how platelet activation and platelet-leukocyte interaction contribute to inflammation in obesity.

METHODS

We evaluated 87 patients with obesity (body mass index >30 kg/m2) in an observational cross-sectional study and investigated mechanisms of thromboinflammatory amplification using coculture models.

RESULTS

We demonstrated increased platelet activation and platelet-monocyte aggregate formation during obesity, which was associated with CD16 and tissue factor (TF) expression on monocytes. Platelet and monocyte activation were associated with metabolic syndrome and markers of increased high cardiovascular risk in obesity. Functional experiments with isolated cells highlighted platelet orchestration of monocyte functions leading to TF expression and proinflammatory mediator secretion. Platelet-monocyte interaction ex vivo reciprocally activated monocytes and platelets, inducing mediator secretion from both cells. Increased TF, CD16, and mediator secretion by monocytes and platelets occurred partially through CD62P-, CD40L-, and integrin αIIb β3-dependent signaling. Finally, conditioned medium from platelet-monocyte cocultures promoted endothelial cell activation through the interleukin 1 receptor.

CONCLUSION

Our data reveal mechanisms involving a reciprocal platelet-monocyte activation amplification loop that was associated with cardiometabolic risk and supports thromboinflammation in obesity.