CITED2 inhibits STAT1-IRF1 signaling and atherogenesis.

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage-mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell-intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as one such cell-intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid-CITED2-deficient mice on the Apoe-/- background have larger atherosclerotic lesions on both control and high-fat/high-cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro-inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ-induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA-mediated knockdown of IRF1 completely reversed elevated pro-inflammatory target gene expression in CITED2-deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1-IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.

Differential contribution of bone marrow-derived infiltrating monocytes and resident macrophages to persistent lung inflammation in chronic air pollution exposure.

Chronic exposure to particulate matter < 2.5µ (PM2.5) has been linked to cardiopulmonary disease. Tissue-resident (TR) alveolar macrophages (AΦ) are long-lived, self-renew and critical to the health impact of inhalational insults. There is an inadequate understanding of the impact of PM2.5 exposure on the nature/time course of transcriptional responses, self-renewal of AΦ, and the contribution from bone marrow (BM) to this population. Accordingly, we exposed chimeric (CD45.2/CD45.1) mice to concentrated PM2.5 or filtered air (FA) to evaluate the impact on these end-points. PM2.5 exposure for 4-weeks induced an influx of BM-derived monocytes into the lungs with no contribution to the overall TR-AΦ pool. Chronic (32-weeks) PM2.5 exposure on the other hand while associated with increased recruitment of BM-derived monocytes and their incorporation into the AΦ population, resulted in enhanced apoptosis and decreased proliferation of TR-AΦ. RNA-seq analysis of isolated TR-AΦ and BM-AΦ from 4- and 32-weeks exposed mice revealed a unique time-dependent pattern of differentially expressed genes. PM2.5 exposure resulted in altered histological changes in the lungs, a reduced alveolar fraction which corresponded to protracted lung inflammation. Our findings suggest a time-dependent entrainment of BM-derived monocytes into the AΦ population of PM2.5 exposed mice, that together with enhanced apoptosis of TR-AΦ and reorganization of transcriptional responses, could collectively contribute to the perpetuation of chronic inflammation.