Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of
Cutibacterium acnes
, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill
C. acnes
. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.
Epigenetic clocks, DNA methylation based chronological age prediction models,
are commonly employed to study age related biology. The error between the predicted
and observed age is often interpreted as a form of biological age acceleration and many
studies have measured the impact of environmental and other factors on epigenetic
age. Epigenetic clocks are fit using approaches that minimize the error between the
predicted and observed chronological age and as a result they reduce the impact of
factors that may moderate the relationship between actual and epigenetic age. Here we
compare the standard methods used to construct epigenetic clocks to an evolutionary
framework of epigenetic aging, the epigenetic pacemaker (EPM) that directly models
DNA methylation as a function of a time dependent epigenetic state. We show that
the EPM is more sensitive than epigenetic clocks for the detection of factors that
moderate the relationship between actual age and epigenetic state (ie epigenetic age).
Specifically, we show that the EPM is more sensitive at detecting sex and cell type
effects in a large aggregate data set and in an example case study is more sensitive
sensitive at detecting age related methylation changes associated with polybrominated
biphenyl exposure. Thus we find that the pacemaker provides a more robust framework
for the study of factors that impact epigenetic age acceleration than traditional clocks
based on linear regression models.
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