Circadian rhythm disruption promotes M1 macrophages polarization exacerbating the inflammatory response in rosacea

Abstract

To explore the role of macrophage polarization induced by circadian rhythm disorder (CRD) in the aggravated inflammatory response of rosacea. The rosacesis-like animal model was established by intradermal injection of Cathelicidin antimicrobial peptide LL-37 (LL37) into the back of mice. HE staining, Western blot and immunofluorescence detection were used to investigate the effect of circadian rhythm disorder on the expression of inflammatory factors and macrophage polarization in rosacea. Overexpression of Brain and Muscle ARNT-Like 1 (Oe-Bmal1) was transfected into HaCaT cells and M0 macrophages treated with LL37 in vitro to investigate the role of Muscle ARNT-Like 1 (Bmal1) on rosacea. In LL37-induced rosacea mice, circadian rhythm disruption (CRD) suppressed the expression of circadian clock proteins, including Bmal1, Circadian Locomotor Output Cycles Kaput (Clock), Period Circadian Protein 1 (Per1), Period Circadian Protein 2 (Per2), Nuclear Receptor Subfamily 1 Group D Member 1 (Rev-erbα), and Retinoic Acid Receptor-Related Orphan Receptor Alpha (RORα), and induced the polarization of macrophages in rosacea-like mice towards the M1 phenotype. Subsequently, the expression of inflammatory factors, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 beta (IL-1β), was promoted, which aggravated the inflammatory response of skin lesions. Over-expression of Bmal1 significantly increased the expression level of clock proteins and inhibited the polarization of macrophages to M1 type, consequently inhibiting the expression of inflammatory factors in the cell model of rosacea. Circadian rhythm disorder may aggravate the inflammatory response of rosacea by affecting macrophage polarization, which indicates that paying attention to regular sleep and rest may be necessary for the treatment and management of rosacea.

Graphical Abstract