Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.

ABSTRACT:

Background

SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation.

Results

We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206⁺ regulatory macrophages that were shown to associate with a therapeutic res

SUBMITTER: Ghiboub M 

PROVIDER: S-EPMC9392322 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature