Sex dimorphism of circulating monocyte subpopulations in the inflammatory response of acute myocardial infarction

Background Complex mechanism of immune responses take effect in human diseases both during pathogenic infection and sterile injury such as acute myocardial infarction (AMI). Monocytes are highly plastic cells that show greater heterogeneity beyond their traditional characterization. Their functionalities comprise inflammatory cytokine release, inflammatory resolution, wound healing and angiogenesis but also tumor progression. In atherosclerosis and AMI their role is well established, but sex-differences remain among the non-resolved research questions. Purpose Unravelling targetable sex-specific differences of circulating monocyte responses from AMI patients compared to healthy subjects. Methods Monocyte subpopulations from male and female AMI patients and healthy controls were isolated and sorted based on their CD14 and CD16 expression. Bulk RNA sequencing was carried out after ribosomal depletion and differentially expressed genes (DEG) were calculated. We performed functional pathway analysis with gene set enrichment analysis (GSEA) and network comparisons using the Cytoscape platform. Selective target validation was performed with quantitative real time PCR. Results Monocyte subpopulations showed a dynamic transcriptome reprogramming during early AMI, which was most pronounced in classical monocytes. Functional enrichment analysis reveals inflammatory priming in male monocytes but associated them also to attenuated inflammatory signaling by upregulating genes such as TNFAIP3 and negative modulation of cell death pathways. Both sexes showed different inflammatory adaptations with female monocytes displaying an earlier and faster shift towards a wound healing phenotype, characterized by upregulation of IL10, MSR1 or CXCR4 whose expression correlated with monocyte counts. This is further supported by distinct expression differences of EGFR ligands with HBEGF being strongly increased only in female monocytes. Male circulating monocytes showed a potential shift in their eicosanoid pathway from inflammatory mediators (prostaglandins and leukotrienes) to resolution-associated lipoxins suggested by increased expression of ALOX5 and HPDG and downregulation of COX2, PTGES3 and LTA4H. Other differences in inflammatory activation were also associated to changes in migration and chemotaxis. Transcriptomic adaptation showed similar patterns to signatures on trauma patients, highlighting a strong similarity of responses to tissue damage under sterile injury in AMI and trauma. Conclusions Sex-specific differences in monocyte responses upon AMI affected both inflammatory and resolutory pathways. These findings emphasize the need for personalized treatment strategies in cardiovascular diseases that consider sex dimorphism in inflammatory activation. We describe potential candidate genes for future validation in a personalized medicine approach such as HBEGF, ADM, CXCR4, ACKR3, IL10, TNFAIP3.