During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall1,2. The observation that circulating monocytes give rise to lesional macrophages3–9 has reinforced the concept that monocyte infiltration dictates macrophage build-up. Recent work indicates, however, that macrophages do not depend on monocytes in some inflammatory contexts10. We therefore revisited the mechanism of macrophage accumulation in atherosclerosis. We show that murine atherosclerotic lesions experience a surprisingly rapid, 4-week, cell turnover. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation via the involvement of scavenger receptor (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.

Most tissues of the body harbor resident macrophages. Yet, macrophages are phenotypically and functionally heterogeneous, a reflection of the diversity of tissue environments in which they reside. In addition to maintaining tissue homeostasis and responding to invading pathogens, macrophages contribute to numerous pathological processes, making them an attractive potential target for therapeutic intervention. To do so, however, will require a detailed understanding of macrophage origins, the mechanisms that maintain them, and their functional attributes in different tissues and disease contexts.Macrophage ontology has long engendered controversy 1,2 . Nevertheless, the concept that tissue macrophages develop exclusively from circulating bone marrow-derived monocytes has prevailed for nearly a half century 3 . Accumulated evidence, however, including recent studies using sophisticated fate-mapping approaches, have determined that some tissue macrophages and their precursors are established embryonically in the yolk sac (YS) and fetal liver before the onset of definitive hematopoiesis [4][5][6][7][8][9][10][11] . Regardless of their origin, tissue macrophages can maintain themselves in adulthood by self-renewal independent of blood monocytes 12,13 .Gene-expression profiling of macrophage populations from several tissues has established that only a small number of transcripts are expressed by all macrophages 14 , indicating the importance of the context provided by the tissue when studying macrophage function in homeostasis and disease. The normal arterial wall contains many tissue resident macrophages that contribute crucially to immunity, tissue homeostasis and wound healing following injury 15. However, the regulatory networks, ancestry and mechanisms that maintain arterial macrophages remain unknown.Using gene expression analysis, we show that arterial macrophages constitute a distinct population among tissue macrophages. Multiple fate mapping approaches demonstrated that arterial macrophages arise embryonically from CX 3 CR1 + precursors and postnatally from bone marrow-derived monocytes that colonize the tissue during a brief period immediately after birth.In adulthood, arterial macrophages were maintained by CX 3 CR1-CX 3 CL1 interactions and local proliferation without significant further contribution from blood monocytes. Self-renewal also sustained arterial macrophages after severe depletion during polymicrobial sepsis, rapidly restoring them to functional homeostasis. ResultsPhenotype and gene expression profiling of arterial macrophages. (Fig. 1a).Principal component analysis revealed a distinct transcriptome in arterial macrophages, which clustered near other macrophage populations including microglia, alveolar macrophages, and splenic red pulp macrophages, as characterized by the Immunological Genome Consortium (Fig. 1b, Supplementary Fig. 1a) 14. Stringent comparison of gene-expression profiles among arterial, brain, alveolar and splenic red pulp macrophages revealed 212 transcripts that were at ...

BackgroundCigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.Methodology and Principal FindingsThe objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.Conclusions and SignificanceThis study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.

Collectively, these data suggest that cigarette smoke exacerbates the inflammatory response to a bacterial challenge via skewed inflammatory mediator expression.

BackgroundChronic obstructive pulmonary disease is a progressive lung disease that is punctuated by periods of exacerbations (worsening of symptoms) that are attributable to viral infections. While rhinoviruses are most commonly isolated viruses during episodes of exacerbation, influenza viruses have the potential to become even more problematic with the increased likelihood of an epidemic.Methodology and Principal FindingsThis study examined the impact of current and potential pharmacological targets namely the systemic corticosteroid dexamethasone and the peroxisome proliferator-activated receptor- gamma agonist pioglitazone on the outcome of infection in smoke-exposed mice. C57BL/6 mice were exposed to room air or cigarette smoke for 4 days and subsequently inoculated with an H1N1 influenza A virus. Interventions were delivered daily during the course of infection. We show that smoke-exposed mice have an exacerbated inflammatory response following infection. While smoke exposure did not compromise viral clearance, precision cut lung slices from smoke-exposed mice showed greater expression of CC (MCP-1, -3), and CXC (KC, MIP-2, GCP-2) chemokines compared to controls when stimulated with a viral mimic or influenza A virus. While dexamethasone treatment partially attenuated the inflammatory response in the broncho-alveolar lavage of smoke-exposed, virally-infected animals, viral-induced neutrophilia was steroid insensitive. In contrast to controls, dexamethasone-treated smoke-exposed influenza-infected mice had a worsened health status. Pioglitazone treatment of virally-infected smoke-exposed mice proved more efficacious than the steroid intervention. Further mechanistic evaluation revealed that a deficiency in CCR2 did not improve the inflammatory outcome in smoke-exposed, virally-infected animals.Conclusions and SignificanceThis animal model of cigarette smoke and H1N1 influenza infection demonstrates that smoke-exposed animals are differentially primed to respond to viral insult. While providing a platform to test pharmacological interventions, this model demonstrates that treating viral exacerbations with alternative anti-inflammatory drugs, such as PPAR-gamma agonists should be further explored since they showed greater efficacy than systemic corticosteroids.