GRN-SORT axis exacerbates the inflammatory response in TREM2-macrophage in acne vulgaris.

Summary: Abstract Body: The inflammatory response plays a crucial role in the formation and progression of acne vulgaris. However, the dysregulation of inflammation-related genes across acne lesions has not been thoroughly investigated. This study aimed to identify dysregulated genes in acne lesions by integrating single-cell RNA sequencing data from early-stage acne with spatial transcriptomics of acne lesions. Our analysis identified 10 genes, including GRN, IL13RA1, IL4R, FAS, and C3, which were consistently altered in all six acne lesions compared to non-lesional skin. Notably, GRN was predominantly expressed by myeloid cells. The cell-cell communication analysis within acne lesions revealed that GRN exerts its pro-inflammatory effects through its receptor, SORT1, in an autocrine manner within TREM2 macrophages. In vitro, treatment of TREM2 macrophages with recombinant GRN protein promoted the expression of pro-inflammatory cytokines (IL-18, IL-1β, TNF-α, IL-6) and chemokines (CCL5, CXCL2). Furthermore, our colony-forming unit killing assays demonstrated that GRN does not exhibit antimicrobial activity or promote the growth of C. acnes, indicating that GRN promotes inflammation through cell-cell interactions rather than directly affecting C. acnes. These findings highlight the critical role of the GRN-SORT1 signaling axis in acne initiation and development, underscoring its potential as a therapeutic target for acne treatment. Min Deng¹, Gregory M. Brewer¹, Samia Almoughrabie², Richard L. Gallo², George W. Agak¹ 1. University of California Los Angeles, Los Angeles, CA, United States. 2. University of California San Diego, La Jolla, CA, United States. Cell Communication Networks and Stromal Biology