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


Klein, Kerstin; Frank-Bertoncelj, Mojca; Karouzakis, Emmanuel; Gay, Renate E; Kolling, Christoph; Ciurea, Adrian; Bostanci, Nagihan; Belibasakis, Georgios N; Lin, Lih-Ling; Distler, Oliver; Gay, Steffen; Ospelt, Caroline (2017). The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance. Journal of autoimmunity, 83:122-133.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2017
Deposited On:30 Aug 2017 16:43
Last Modified:31 Aug 2017 07:31
Publisher:Elsevier
ISSN:0896-8411
Publisher DOI:https://doi.org/10.1016/j.jaut.2017.07.001
PubMed ID:28701277

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