N2-Polarized Neutrophils Reduce Inflammation in Rosacea by Regulating Vascular Factors and Proliferation of CD4+ T Cells

The infiltration of neutrophils is implicated in rosacea, which is a common chronic inflammatory facial disease. This study explores the biological function of neutrophils and their underlying mechanism in rosacea. A rosacea-like mouse model was established to explore the polarization of neutrophils. RNA sequencing was used to investigate the underlying mechanisms. Our results show that neutrophils partly switched to N2 phenotypes in both patients with rosacea and rosacea-like mouse models. The rosacea-like phenotype and inflammation in both a genetic mutation (Genista mice) and the Gr-1 antibody‒induced neutropenia mice were significantly aggravated compared with that in the control groups. In vitro, lipopolysaccharide + IFN-γ and IL4 stimulation of neutrophils successfully induced the N1 and N2 polarization of neutrophils, respectively. Replenishment of N2 neutrophils in the lesions of wild-type and Genista mice ameliorated the rosacea-like phenotype and inflammation. RNA sequencing suggested that N2 neutrophils relieved the rosacea-like phenotype, possibly by regulating the expression of blood circulation‒associated factors, such as ACE, AGTR2, and NOS1. Finally, N2 neutrophils regulated the proliferation of CD4+ lymphocytes, which could explain the remission of inflammation in mice. Our results suggest that N2 polarization of neutrophils in rosacea exerts anti-inflammatory effects by regulating vascular factors and proliferation of CD4+ T cells.