A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.

How a local infection triggers systemic humoral immunity remains unclear. Here we identify farnesyl pyrophosphate (FPP), a mevalonate pathway metabolic intermediate1, as an endogenous alarmin that enhances IgG antibody responses through keratinocyte-derived IL-6 and CCL20. This signalling axis potentiates the differentiation of T follicular helper cells and migratory dendritic cells2,3. FPP accumulates within keratinocytes after infection or ultraviolet irradiation through the activation of the mevalonate pathway mediated by the unfolded protein response-SREBF pathway, amplifying germinal centre (GC) responses in draining lymph nodes. Mechanistically, accumulated FPP in the cytosol engages transient receptor potential vanilloid 3 (TRPV3) by binding to its intracellular domains, inducing Ca2+ influx that subsequently activates the calmodulin-calcineurin-NFAT and PYK2-RAS-ERK pathways to enhance IL-6 and CCL20 production. This FPP-TRPV3-IL-6/CCL20-GC axis potentiates pathogen-specific antibody production, conferring protection in wild-type but not TRPV3-deficient mice. Single-cell RNA-sequencing analyses of systemic lupus erythematosus (SLE) skin lesions and pathogen-infected mouse skin demonstrate hyperactivation of this signalling axis, particularly in the TRPV3high keratinocyte subset. In mouse models of SLE, the activation of this axis correlates with exacerbated disease pathology. Thus, FPP potentiates systemic humoral immunity through the TRPV3-IL-6/CCL20-GC signalling axis, providing insights for the development of vaccine adjuvants and potential therapeutics for SLE.