Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders

Background: Non-infectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear.Objective: To understand spatial gene expression characteristics in these disorders.Methods: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion.Results: CS is characterized by a polarized, spatially organized T helper (Th) 1 predominant response with classical macrophage activation. GA is characterized by a mixed, but spatiallyorganized pattern of Th1 and Th2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of Th1, Th2, and Th17 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation.Conclusions: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.Clinical Implication: The molecular profiles of these disorders imply multiple avenues for novel therapeutic intervention and begin to shed light on the immunologic differences amongst disorders.