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The apoAI mimetic 4F was designed to inhibit atherosclerosis by improving HDL. We reported that treating tight skin (Tsk −/+ ) mice, a model of systemic sclerosis (SSc), with 4F decreases inflammation and restores angiogenic potential in Tsk −/+  hearts. Interferon regulating factor 5 (IRF5) is important in autoimmunity and apoptosis in immune cells. However, no studies were performed investigating IRF5 in myocardium. We hypothesize that 4F differentially modulates IRF5 expression and activation in Tsk −/+  hearts. Posterior wall thickness was significantly increased in Tsk −/+  compared to C57Bl/6J (control) and Tsk −/+  mice with 4F treatment assessed by echoradiography highlighting reduction of fibrosis in 4F treated Tsk −/+  mice. IRF5 in heart lysates from control and Tsk/+ with and without 4F treatment (sc, 1 mg/kg/d, 6–8 weeks) was determined. Phosphoserine, ubiquitin, ubiquitin K 63  on IRF5 were determined on immunoprecipitates of IRF5. Immunofluorescence and TUNEL assays in heart sections were used to determine positive nuclei for IRF5 and apoptosis, respectively. Fluorescence-labeled streptavidin (SA) was used to determine endothelial cell uptake of biotinylated 4F. SA-agarose pulldown and immunoblotting for IRF5 were used to determine 4F binding IRF5 in endothelial cell cytosolic fractions and to confirm biolayer interferometry studies. IRF5 levels in Tsk −/+  hearts were similar to control. 4F treatments decrease IRF5 in Tsk −/+  hearts and decrease phosphoserine and ubiquitin K 63  but increase total ubiquitin on IRF5 in Tsk −/+  compared with levels on IRF5 in control hearts. 4F binds IRF5 by mechanisms favoring association over dissociation strong enough to pull down IRF5 from a mixture of endothelial cell cytosolic proteins. IRF5 positive nuclei and apoptotic cells in Tsk −/+  hearts were increased compared with controls. 4F treatments decreased both measurements in Tsk −/+  hearts. IRF5 activation in Tsk −/+  hearts is increased. 4F treatments decrease IRF5 expression and activation in Tsk −/+  hearts by a mechanism related to 4F’s ability to bind IRF5.

4F Decreases IRF5 Expression and Activation in Hearts of Tight Skin Mice