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Macrophages are abundant in atherosclerotic plaques and are a pivotal cell type in plaque formation and progression. But how do they get there? Filip Swirski and his colleagues show that, contrary to most previous work that has emphasized the importance of monocyte recruitment from the blood, most macrophages in established lesions are generated by local macrophage proliferation, which depends on the SR-A scavenger receptor. During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall 1 , 2 . The observation that circulating monocytes give rise to lesional macrophages 3 , 4 , 5 , 6 , 7 , 8 , 9 has reinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts 10 . We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.

Damaged erythrocytes accumulate in various pathological conditions, such as hemolytic anemia, anemia of inflammation, and sickle cell disease. In mice challenged with damaged erythorcytes, a monocyte subset migrates to the liver (but not to the spleen), and this subset differentiates into a transient macrophage population that removes the damaged erythrocytes, thus preventing organ damage. Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal 1 . In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity 2 , 3 . Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1 )-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1 + Tim-4 neg macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4) high Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2 ). The spleen, likewise, recruits iron-loaded Ly-6C high monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression. Empagliflozin reduces blood glucose levels via inhibition of the sodium glucose cotransporter 2 (SGLT-2) in the kidney and has been shown to lead to a marked reduction in cardiovascular events in humans. To determine whether glucose lowering by empagliflozin accelerates atherosclerosis regression in a mouse model, male C57BL/6J mice were treated intraperitoneally with LDLR- and SRB1- antisense oligonucleotides and fed a high cholesterol diet for 16 weeks to induce severe hypercholesterolemia and atherosclerosis progression . At week 14 all mice were rendered diabetic by streptozotocin (STZ) injections. At week 16 a baseline group was sacrificed and displayed substantial atherosclerosis of the aortic root. In the remaining mice, plasma cholesterol was lowered by switching to chow diet and treatment with LDLR sense oligonucleotides to induce atherosclerosis regression . These mice then received either empagliflozin or vehicle for three weeks. Atherosclerotic plaques in the empagliflozin treated mice were significantly smaller, showed decreased lipid and CD68 + macrophage content, as well as greater collagen content. Proliferation of plaque resident macrophages and leukocyte adhesion to the vascular wall were significantly decreased in empagliflozin-treated mice. In summary, plasma glucose lowering by empagliflozin improves plaque regression in diabetic mice.

Recognition and clearance of a bacterial infection are fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from Bla B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases.

Extracellular adenosine-5′-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X 4 and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X 4 -axis in atherosclerosis. Expression of P2X 4 was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X 4 in atherosclerosis, P2X 4 -deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X 4 -deficient mice developed smaller atherosclerotic lesions compared to P2X 4 -competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X 4 -deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X 4 -deficient mice. Moreover, bone marrow derived macrophages isolated from P2X 4 -deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1β (IL-1β) and IL-6. Additionally, P2X 4 -deficient mice shared a lower proportion of pro-inflammatory Ly6C high monocytes and a higher proportion of anti-inflammatory Ly6C low monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X 4 expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study’s findings for human atherosclerosis. Collectively, P2X 4 deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X 4 as a potential therapeutic target in the fight against atherosclerosis.

Macrophages play a central role in tuberculosis, both in bacterial persistence and tissue pathology. Body weight and a dysregulated lipid metabolism profoundly affect disease progression and survival. Yet, the relationship between lipid metabolism and mycobacterial immunity is still poorly understood. Accordingly, this study investigated the influence of cholesterol and lipoproteins on macrophage responses to mycobacteria, in particular the formation of multinucleated giant cells (MGC), which are key components of granulomas and involved in the containment of mycobacteria. We found that low-density lipoprotein (LDL) cholesterol was essential for the transformation of macrophage progenitors into MGCs in vitro, independent of the oxidation status. In contrast to these direct lipid effects on macrophage transformation, a lipid-rich diet to mice, which is known to elevate cholesterol levels in the blood, did not prime the MGC forming potential of bone-marrow progenitor cells. In conclusion, LDL promotes the mycobacteria-specific macrophage transformation, however, this effect appears to depend on tissue lipid availability rather than priming in the bone marrow.

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions. Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.

Myocardial infarction (MI) and subsequent heart failure are frequently accompanied by chronic kidney disease, further impairing outcomes and complicating treatment. To better understand heart-kidney crosstalk, we used RNA sequencing data to infer interorgan signalling after experimentally induced MI in mice, focusing on secreted biomolecules and interorgan cross talk that may drive cardiorenal syndrome (CRS). To assess acute and chronic effects, we examined kidneys at 5d and 28d post-MI, evaluating changes in renal gene expression and fibrosis. During the acute phase 5d post-MI, several genes inferred to target kidney receptors were highly upregulated in the cardiac infarct zone, with Postn and Spp1 being the most probable ligands. However, only minor changes in gene expression were detected in the kidney 5d post-MI. At 28d post-MI, renal fibrosis and the number of differentially expressed genes (DEGs) in the kidney increased. Gene ontology enrichment suggested metabolic adaptions as part of a long-term response. Based on upregulated DEGs in kidney 28d post-MI, we suggest two kidney-to-heart interactions: Slitrk6-Ptprs and Gdf15-Tgfbr2. In vitro, GDF-15 treatment of human cardiac fibroblasts induced pro-fibrotic gene expression, mirroring in vivo changes in the heart. Our data suggest that MI in mice elicits minimal acute response in kidney but triggers chronic transcriptional and pro-fibrotic changes in kidney, potentially driven by altered renal metabolism. The inference of interorgan signalling molecules such as GDF-15 points towards candidate mediators of CRS and provides a basis for future mechanistic and clinical studies.

BackgroundInflammation drives atherosclerosis and its complications. Anti-inflammatory therapy with interleukin 1 beta (IL-1β) antibody reduces cardiovascular events in patients with elevated high-sensitive C-reactive protein (hsCRP). This study aims to identify the share of patients with coronary heart disease (CHD) and residual inflammation who may benefit from anti-inflammatory therapy.MethodshsCRP and low-density lipoprotein (LDL) levels were determined in 2741 all-comers admitted to the cardiological ward of our tertiary referral hospital between June 2016 and June 2018. Patients without CHD, with acute coronary syndrome, chronic or recurrent systemic infection, use of immunosuppressant or anti-inflammatory agents, chronic inflammatory diseases, chemotherapy, terminal organ failure, traumatic injury and pregnancy were excluded.Results856 patients with stable CHD were included. 42.7% of those had elevated hsCRP ≥ 2 mg/l. Within the group of patients with LDL-cholesterol < 70 mg/dl, 30.9% shared increased hsCRP indicating residual inflammation. After multivariate adjusted backward selection elevated Lipoprotein (a) (OR 1.61, p = 0.048), elevated proBNP (OR 2.57, p < 0.0001), smoking (OR 1.70, p = 0.022), and obesity (OR 2.28, p = 0.007) were associated with elevated hsCRP. In contrast, the use of ezetimibe was associated with normal hsCRP (OR 0.51, p = 0.014). In the subgroup of patients with on-target LDL-cholesterol < 70 mg/dl, backward selection identified elevated proBNP (OR 3.49, p = 0.007) as independent predictor of elevated hsCRP in patients with LDL-cholesterol < 70 mg/dl.ConclusionOne-third of all-comers patients with CHD showed increased levels of hsCRP despite a LDL-cholesterol < 70 mg/dl potentially qualifying for an anti-inflammatory therapy. Elevated proBNP is an independent risk factor for hsCRP elevation.Graphic abstract

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.