TREM2 macrophages induced by human lipids drive inflammation in acne lesions

Abstract

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.

The biology of TREM receptors

“…Increased sebum secretion, along with growth of the commensal Cutibacterium acnes and obstruction of the hair follicle, causes inflammation and clinical manifestations of acne 172 . Multipronged analysis of acne lesions revealed TREM2 + macrophages adjacent to hair follicles and sebaceous glands 173 . TREM2 + macrophages were close to the epithelium lining the hair follicle and sebaceous glands and expressed a lipid metabolic programme similar to that found in foamy macrophages of atherosclerotic lesions (Table 1 ).…”

Heterogeneity of macrophages in atherosclerosis revealed by single‐cell RNA sequencing

“…These Trem2 hi macrophages appeared to be foam cells, but they did not produce the inflammatory cytokines or chemokines associated with atherosclerosis. 66,74 Therefore, Trem2 hi macrophage was a better definition, and these cells were predominantly found in atherosclerotic but almost absent in healthy aortas. In other words, the definition of the new subtype Trem2 hi macrophages provided a more comprehensive understanding of its function and gradually replaced the definition of foamy macrophages in recent studies.…”

Acne Comorbidities

“…32 The latest data indicate that the pathogenesis of acne shares features of other metabolic diseases in which TREM2 macrophages and lipid dysregulation are prominent. 68 Acne and the above diseases have many common pathogenesis mechanisms, and there is the possibility of comorbidity. The form of their comorbidity may be concurrent existence, sequential existence, or mutually-causal existence.…”