Priming of human monocytes by β-glucan and obesity-associated factors: modifications to global DNA methylation, gene expression, phenotype and function.

INTRODUCTION

Monocytes play a critical role in regulating immune response to exogenous and endogenous challenge. Recent studies have shown exogenous stimuli can induce metabolic, epigenetic and phenotypic changes in monocytes that reprogramme or 'prime' them to react with an altered response to subsequent stimuli. Obesity is associated with immune dysfunction. However, the ability of endogenous compounds associated with obesity to prime human monocytes and thereby modulate subsequent response remains to be investigated.

METHODS AND

RESULTS

In this study, human monocytes from non-obese males were utilized. Monocytes exposed to primary exogenous stimuli (β-glucan), but not endogenous stimuli (oxLDL, leptin, 17β-estradiol), demonstrated an altered phenotype (increased CD11b, PD-L1 expression) in response to SK-MEL-28 melanoma cells. In contrast, monocytes primed with oxLDL, but not β-glucan, exhibited an increased rate of superoxide production in response to secondary stimulation with phorbol 12-myristate 13-acetate, and enhanced matrix metalloprotease 9 activity in response to secondary stimulation with lipopolysaccharide. Bulk RNAseq analysis of non-primed monocytes and monocytes primed with 17β-estradiol or oxLDL also showed sustained differential expression of genes related to immune function, metabolism and protein modification. Moreover, mass spectrometry analysis showed that monocytes primed with β-glucan or oxLDL exhibited sustained modifications to global DNA methylation.

CONCLUSIONS

These results provide the first steps in understanding the functional consequences of monocyte reprogramming by obesity-related factors, and the potential pathways that govern them.