The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance

•Synovial fibroblasts (SF) and macrophages exhibit distinct types of LPS tolerance.•Pro-inflammatory and matrix degrading genes are non-tolerizable in SF.•Anti-viral response genes are tolerizable in SF and are regulated by CREB1.•Epigenetic configurations in non-tolerizable genes differ in SF and monocytes.•The epigenetic configuration in tolerizabe genes is similar in SF and monocytes.

Synovial fibroblasts (SF) drive inflammation and joint destruction in chronic arthritis. Here we show that SF possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In SF and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable. Repeated stimulation of SF with LPS resulted in loss of activating histone marks only in promoters of tolerizable genes. The epigenetic landscape at promoters of tolerizable genes was similar in unstimulated SF and monocytes, whereas the basal configuration of histone marks profoundly differed in genes that were non-tolerizable in SF only. Our data suggest that the epigenetic configuration at gene promoters regulates cell-specific LPS-induced responses and primes SF to sustain their inflammatory response in chronic arthritis.