LPS stimulation reveals male and female dimorphism in human iPSC-derived macrophages

Clinical disparities in the inflammatory responses between males and females have been reported for decades, revealing sex-biased disease severity and patient outcomes. However, the underlying mechanisms driving these differences are understudied and poorly understood, despite the growing potential for improved diagnoses and treatment strategies. In this study, we used male and female iPSC-derived macrophages to identify transcriptomic changes in response to the common bacterial antigen lipopolysaccharide (LPS). Bulk RNA sequencing identified 67 genes differentially expressed between male and female macrophages in the absence of inflammation, the majority of which mapped to the sex chromosomes. This sexual dimorphism was amplified by LPS stimulation, with genes predominantly located on autosomes, leading to divergent patterns in secreted protein production that were consistent with clinical findings following LPS exposure. Although future validation with a larger patient cohort is needed, these data collectively suggest that iPSC-derived macrophages can serve as a meaningful tool for understanding and improving treatment of sex-biased pathophysiological conditions.