OC 38.2 - Platelet CLEC-2 protects liver function from septic injury by inducing macrophage activation

Background: Multiple organ failure during sepsis is a progressive failure of several interdependent organ systems. Liver dysfunction occurs early during sepsis, and is directly associated with the patient’s death. The platelet receptor CLEC-2 prevents inflammation-induced vascular leakage and hemorrhage, but the underlying mechanism by which CLEC-2 protects liver function during sepsis is unknown.

Aims: It is of great clinical significance to further clarify the pathogenesis of sepsis, and to establish a new targeted intervention.

Methods: Mice lacking CLEC-2 in platelets or ligand PDPN in myeloid cells, and littermates were injected with E. coli. The molecular mechanism of CLEC-2 and PDPN regulation of liver injury during sepsis was studied by single-cell sequencing.

Results: Our experiment revealed the presence of CD41-positive particles, on the outer side of the blood vessel wall in mouse liver tissue after stimulation with E. coli. Transcriptome sequencing of peripheral blood from sepsis patients revealed platelet activation and binding to macrophages (Figure 1). Single-cell sequencing analysis of liver from septic mice showed that CLEC-2 regulates high expression of JMJD3 in macrophages. Platelets induces activation of the STAT1/JMJD3 pathway in macrophages through CLEC-2/PDPN. Immunoprecipitation showed that phosphorylated JMJD3 in macrophages binds directly to the nuclear receptor PPARα and induces downstream signaling (Figure 2). We searched for genes in single-cell data and found that Irf4 is one of the direct targets of JMJD3.

Conclusion(s): The activated platelets penetrate the hepatic blood sinusoidal capillaries and interact with PDPN-expressing liver macrophages via CLEC-2, activating the STAT1/JMJD3 pathway, promoting nuclear entry of JMJD3 and binding to PPARα, which in turn promotes Irf4 transcription and expression of anti-inflammatory factors, alleviating liver injury caused by sepsis. These findings reveal an important function of platelet CLEC-2 in regulation of liver macrophage activation during sepsis and a novel mechanism to protect liver function from septic injury.