Plasticizers escape from medical devices used in cardiac surgery into patient blood and tissues. Increased di-ethylhexyl phthalate (DEHP) exposure is correlated with chronic inflammation in vivo and increased cytokine release in exposed monocytes in vitro. To determine if acute phthalate exposure enhanced inflammation in a model of cardiac damage, we measured immune cell infiltration, inflammasome expression and cardiac function in male C57bl/6 N mice exposed to phthalates during recovery from a surgically-induced myocardial infarction (MI). Phthalate exposed mice had greater neutrophil and pro-inflammatory macrophage infiltration, greater cardiac dilation and reduced cardiac function when compared with control mice. The greater expression of NLRP3 and NLRP6, but not AIM2 or P2xR7, in the infarcts of phthalate exposed versus control mice suggests a selectivity in pattern recognition receptor activation. Treatment of human THP-1 macrophages with phthalates revealed increased NLRP3 and NLRP6 expression and induction of a pro-inflammatory macrophage population. Pre-treatment with the PPARγ antagonist GW9662 reduced these increases. An increase in expression of IL-1R, MyD88 and IRAK4 in infarcts of phthalate exposed mice and THP-1 cells argues for greater priming downstream of IL-1R signaling and increased susceptibility for inflammasome activation. Importantly, these effects were moderated in vivo when phthalate exposure was reduced by 90% and when the NLRP3 antagonist MCC950 was co-administered. Our study suggests that reductions in phthalate exposure, which might be realized using plasticizers with a reduced ability to leach out from plastic, or short-term treatment with an anti-inflammasome may improve healing post-surgery.
Keywords: Macrophage; Myocardial infarction; NLPR3 inflammasome; Phthalates.
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