Aims Platelets play a key role in the pathophysiology of coronary artery disease (CAD) and patients with enhanced platelet activation are at increased risk to develop adverse cardiovascular events. Beyond reliable cardiovascular risk factors such as dyslipoproteinaemia, significant changes of platelet lipids occur in patients with CAD. In this study, we investigate the platelet lipidome by untargeted liquid chromatography–mass spectrometry, highlighting significant changes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. Additionally, we classify the platelet lipidome, spotlighting specific glycerophospholipids as key players in ACS patients. Furthermore, we examine the impact of significantly altered lipids in ACS on platelet-dependent thrombus formation and aggregation. Methods and results In this consecutive study, we characterized the platelet lipidome in a CAD cohort (n = 139) and showed significant changes of lipids between patients with ACS and CCS. We found that among 928 lipids, 7 platelet glycerophospholipids were significantly up-regulated in ACS, whereas 25 lipids were down-regulated compared to CCS. The most prominent up-regulated lipid in ACS, PC18:0 (PC 10:0-8:0), promoted platelet activation and ex vivo platelet-dependent thrombus formation. Conclusions Our results reveal that the platelet lipidome is altered in ACS and up-regulated lipids embody primarily glycerophospholipids. Alterations of the platelet lipidome, especially of medium chain lipids, may play a role in the pathophysiology of ACS.

We hypothesized that most patients with severe pulmonary COVID-19 were exposed to cough aerosols. Among patients that were almost 100% certain which person infected them, only 14 out of 38 overall, and 9 out of 25 hospitalized patients requiring supplemental oxygen, were infected by someone who coughed, which did not support our hypothesis. Talking, especially with a loud voice, could be an alternative source generating SARS-CoV-2 aerosols. Further research is needed to determine how SARS-CoV-2 spreads. Avoiding to talk when you are not wearing your mask and not talking with a loud voice, ‘voice etiquette’, could be other public health interventions worthwhile exploring.

To fulfil its orchestration of immune cell trafficking, a network of chemokines and receptors developed that capitalizes on specificity, redundancy, and functional selectivity. The discovery of heteromeric interactions in the chemokine interactome has expanded the complexity within this network. Moreover, some inflammatory mediators, not structurally linked to classical chemokines, bind to chemokine receptors and behave as atypical chemokines (ACKs). We identified macrophage migration inhibitory factor (MIF) as an ACK that binds to chemokine receptors CXCR2 and CXCR4 to promote atherogenic leukocyte recruitment. Here, we hypothesized that chemokine–chemokine interactions extend to ACKs and that MIF forms heterocomplexes with classical chemokines. We tested this hypothesis by using an unbiased chemokine protein array. Platelet chemokine CXCL4L1 (but not its variant CXCL4 or the CXCR2/CXCR4 ligands CXCL8 or CXCL12) was identified as a candidate interactor. MIF/CXCL4L1 complexation was verified by co-immunoprecipitation, surface plasmon-resonance analysis, and microscale thermophoresis, also establishing high-affinity binding. We next determined whether heterocomplex formation modulates inflammatory/atherogenic activities of MIF. Complex formation was observed to inhibit MIF-elicited T-cell chemotaxis as assessed by transwell migration assay and in a 3D-matrix-based live cell-imaging set-up. Heterocomplexation also blocked MIF-triggered migration of microglia in cortical cultures in situ, as well as MIF-mediated monocyte adhesion on aortic endothelial cell monolayers under flow stress conditions. Of note, CXCL4L1 blocked binding of Alexa-MIF to a soluble surrogate of CXCR4 and co-incubation with CXCL4L1 attenuated MIF responses in HEK293-CXCR4 transfectants, indicating that complex formation interferes with MIF/CXCR4 pathways. Because MIF and CXCL4L1 are platelet-derived products, we finally tested their role in platelet activation. Multi-photon microscopy, FLIM-FRET, and proximity-ligation assay visualized heterocomplexes in platelet aggregates and in clinical human thrombus sections obtained from peripheral artery disease (PAD) in patients undergoing thrombectomy. Moreover, heterocomplexes inhibited MIF-stimulated thrombus formation under flow and skewed the lamellipodia phenotype of adhering platelets. Our study establishes a novel molecular interaction that adds to the complexity of the chemokine interactome and chemokine/receptor-network. MIF/CXCL4L1, or more generally, ACK/CXC-motif chemokine heterocomplexes may be target structures that can be exploited to modulate inflammation and thrombosis.

Half a year after the emergence of COVID-19, research is still going on to gain insight in the importance of different SARS-CoV-2 transmission routes and their impact on the clinical picture of COVID-19. Our findings suggest that coughing is not as important for transmission as initially anticipated and we discuss the potentially important role for loud conversation as a driver for transmission.

To fulfil its orchestrating function in immune cell trafficking, a network of chemokines and receptors capitalizes on specificity, redundancy, and functional selectivity. The discovery of heteromeric interactions in the chemokine interactome has expanded the complexity within the network. Moreover, some inflammatory mediators, not structurally linked to classical chemokines, bind to chemokine receptors and behave as atypical chemokines (ACKs). We identified macrophage migration inhibitory factor (MIF) as an ACK that binds to the chemo­kine receptors CXCR2 and CXCR4 to promote atherogenic leukocyte recruitment. Here, we hypothesized that chemokine-chemokine interactions extend to ACKs and that MIF may form hetero­complexes with classical chemokines. We tested this hypothesis by an unbiased chemokine protein array. The platelet chemokine CXCL4L1, but not its variant CXCL4 or the CXCR2/CXCR4 ligands CXCL8 or CXCL12, was identified as a candidate interactor. MIF/CXCL4L1 complexation was verified by co-immunoprecipitation, surface plasmon-resonance analysis, and microscale thermo­phoresis, also establishing high-affinity binding. We next determined whether heterocomplex formation modulates inflammatory/atherogenic activities of MIF. Complex formation abrogated MIF-elicited T-cell chemotaxis as assessed in a 3D-matrix-based live cell-imaging set-up. Hetero­complexation also blocked MIF-triggered migration of microglia in cortical cultures in situ . Of note, CXCL4L1 blocked the binding of Alexa-MIF to a soluble surrogate of CXCR4 and co-incubation with CXCL4L1 attenuated MIF responses in HEK293-CXCR4 transfectants, indicating that complex formation interferes with MIF/CXCR4 pathways. As MIF and CXCL4L1 are platelet products, we finally tested their role in platelet activation. Multi-photon microscopy, FLIM-FRET, and proximity-ligation assay visualized heterocomplexes in platelet aggregates and clinical human thrombus sections. Moreover, heterocomplexes inhibited MIF-stimulated throm­bus formation under flow and skewed the lamellipodia phenotype of adhering platelets. Our study establishes a novel molecular interaction, adding to the complexity of the chemokine interactome and chemokine/receptor-network. MIF/CXCL4L1, or more generally, ACK/CXC-motif chemokine heterocomplexes may be target structures to modulate inflammation and thrombosis.