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      Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression

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          Abstract

          <p class="first" id="d2707410e269">Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6C <sup>hi</sup> ( <i>Ccr2 <sup>–/–</sup> </i> or <i>Cx3cr1 <sup>–/–</sup> </i>) or patrolling Ly6C <sup>lo</sup> ( <i>Ccr5 <sup>–/–</sup> </i>) monocytes. Atherosclerotic plaques transplanted into WT or <i>Ccr5 <sup>–/–</sup> </i> recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into <i>Ccr2 <sup>–/–</sup> </i> or <i>Cx3cr1 <sup>–/–</sup> </i> recipients lacked this regression signature. The requirement of recipient Ly6C <sup>hi</sup> monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6C <sup>hi</sup> inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression. </p>

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          Most cited references28

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          Development of monocytes, macrophages, and dendritic cells.

          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.

            A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (T(H)2)-related pathologies under the control of the archetypal T(H)2 cytokine interleukin-4 (IL-4) and was a fundamental component of T(H)2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
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              Anti-inflammatory therapy in chronic disease: challenges and opportunities.

              A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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                Author and article information

                Journal
                Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                June 26 2017
                June 26 2017
                : 127
                : 8
                : 2904-2915
                Article
                10.1172/JCI75005
                5531402
                28650342
                b524656d-0344-4cc7-b07e-67d8656d5dc4
                © 2017
                History

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