Ribosomal Protein L13a Deficiency in Macrophages Promotes Atherosclerosis by Limiting Translation Control-Dependent Retardation of Inflammation

Abstract

Objective Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of LPS-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high fat diet-induced atherosclerosis. Approach and Results We bred the macrophage-specific L13a knockout mice L13a Flox+/+ Cre+/+ onto apoE−/− background and generated the experimental double knockout (KO) mice L13a Flox+/+ Cre+/+ apoE−/−. L13a Flox+/+ Cre−/− mice on apoE−/− background were used as controls. Control and KO mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the KO mice. Severity of atherosclerosis in KO mice was accompanied by thinning of the smooth muscle cell (SMC) layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from KO mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control. Conclusion Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apoE−/− mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis.

L13a-dependent translational control in macrophages limits the pathogenesis of colitis

“…We previously used a cellular model of human monocytes 13 and an animal model of myeloid-specific L13a KO mice 15 to show the ability of L13a-dependent translational silencing to block the translation of different chemokine and chemokine receptors harboring GAIT elements in the 3'UTRs of the mRNA. Using animal models of LPS-induced endotoxemia 15 and high-fat diet-induced atherosclerosis, 16 we also showed the potential of this mechanism to resolve physiological inflammation. These studies are consistent with emerging evidence from other groups regarding the importance of translational control in innate immunity and inflammation.…”

“…The polysomes were resolved, and the chemokine mRNAs were identified in the fractions using previously established methods. 15,16 GAIT element-mediated translational silencing was determined using a previously reported protocol. 15 Identification of live bacteria in the circulation of the DSStreated mice Blood was isolated from mice fed 3% DSS (w/v) in the drinking water through cardiac puncture into tubes containing 0.1 M EDTA.…”

“…9,12 To determine the physiological significance of this silencing mechanism, we generated myeloid-specific L13a-knockout (KO) mice. In models of lipopolysaccharide-induced endotoxemia 15 and high-fat diet-induced atherosclerosis, 16 these KO mice displayed severe inflammation, unregulated chemokine expression and significantly increased disease susceptibility compared with isogenic control mice that had intact L13a function.…”

“…5,6 IBD is exacerbated through inappropriate immune responses elicited in the host mucosa via commensal populations of bacteria, which disrupt intestinal homeostasis and further damage the mucosal barrier. 7 Using cultured cells [8][9][10][11][12][13][14] and live mouse models, 15,16 we uncovered an endogenous mechanism in macrophages and monocytes that restrains inflammation through the translational silencing of a group of chemokines and chemokine receptors. 13 This process relies on the phosphorylationdependent release of the L13a protein from the 60S ribosomal subunit 9 and its assembly into a multi-protein RNA-binding complex named the IFN-c-activated inhibitor of translation (GAIT) complex.…”

Atherosclerosis

“…68 Using this approach with mice expressing LysM Cre recombinase, Basu et al 69 found that genetic depletion of ribosomal protein L13a in macrophages augmented atherosclerosis in mice.…”