Macrophage proliferation

About: Macrophage proliferation is a research topic. Over the lifetime, 663 publications have been published within this topic receiving 23018 citations.

Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation

Abstract: 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.

Local proliferation dominates lesional macrophage accumulation in atherosclerosis

Abstract: During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall. The observation that circulating monocytes give rise to lesional macrophages 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. 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.

NF-κB: pivotal mediator or innocent bystander in atherogenesis?

Abstract: Atherosclerosis and its clinical manifestations of heart attack, stroke, and peripheral vascular insufficiency are a major cause of morbidity and mortality among both men and women Multiple risk factors including hypertension, diabetes mellitus, smoking, and lipoprotein disorders are involved in the pathogenesis of this chronic inflammatory disease of arteries The development of early atherosclerotic lesions can be subdivided into initiation (formation of small fatty streaks), expansion (vertical and lateral growth and coalescence of fatty streaks), and progression to plaques (intimal smooth muscle cell recruitment, collagen deposition, and formation of a fibrous cap) (reviewed in ref1) During the initiation and expansion of fatty streaks, circulating monocytes are recruited to the arterial intima where they are transformed into lipid-engorged macrophage foam cells The arterial endothelium in these regions is activated and expresses inducible leukocyte adhesion molecules and chemokines Production of cytokines and growth factors within lesions may amplify monocyte recruitment, stimulate macrophage proliferation, and induce migration of smooth muscle cells from the media to the intima of the vessel Intimal smooth muscle cells deposit collagen and other ECM proteins, leading to the formation of a fibrous cap Although clinically significant complications of atherosclerosis, such as plaque ulceration, rupture, and thrombosis, occur in established or advanced atherosclerotic plaques, understanding the mechanisms of early lesion formation offers the hope of intervening to delay or prevent lesion progression and complications A select set of transcription factors may be critical in both the initiation and expansion of lesions, as well as in protecting the vessel wall from the formation of atherosclerotic lesions In this overview, we will focus on one transcription factor, NF-κB, whose activation has been linked to the onset of atherosclerosis NF-κB is composed of members of the Rel family that share a 300 amino acid region, known as the Rel homology domain, which mediates dimerization, nuclear translocation, DNA binding, and interaction with NF-κB inhibitors (reviewed in ref2) Activation of NF-κB is controlled by a family of inhibitors, or IκBs, that bind to NF-κB dimers and mask the nuclear localization sequence of NF-κB, thus retaining the entire complex in the cytoplasm Diverse stimuli activate NF-κB, through the phosphorylation and activation of the IκB kinase (IKK) complex This complex consists of IKK-α and IKK-β heterodimers, a number of IKK-γ subunits, and possibly other components that have less certain significance The activated IKK complex specifically phosphorylates the IκBs, which are then rapidly polyubiquitinated, targeting them for degradation by the proteosome Following release from the inhibitor, NF-κB dimers translocate from the cytoplasm to the nucleus, where they bind target genes and stimulate transcription (Figure ​(Figure1)1) NF-κB activates a variety of target genes relevant to the pathophysiology of the vessel wall, including cytokines, chemokines, and leukocyte adhesion molecules, as well as genes that regulate cell proliferation and mediate cell survival NF-κB also activates the IκBα gene, thus replenishing the cytoplasmic pool of its own inhibitor Restored expression of IκB-α decreases NF-κB activation and diminishes expression of NF-κB–dependent genes The NF-κB/IκB-α autoregulatory system ensures that the induction of NF-κB is transient and that the activated cell returns to a quiescent state Physiological modulation and pathological activation of the NF-κB system may contribute to the changes in gene expression that occur during atherogenesis Figure 1 Schematic representation of NF-κB as an integrator in atherogenesis Many of the diverse agents associated with the onset of lesion formation interact with specific receptors Angiotensin II (Ang II), cytokines, advanced glycosylation end products

Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells

Abstract: CSF-1 is broadly expressed and regulates macrophage and osteoclast development. The action and expression of IL-34, a novel CSF-1R ligand, were investigated in the mouse. As expected, huIL-34 stimulated macrophage proliferation via the huCSF-1R, equivalently to huCSF-1, but was much less active at stimulating mouse macrophage proliferation than huCSF-1. Like muCSF-1, muIL-34 and a muIL-34 isoform lacking Q81 stimulated mouse macrophage proliferation, CSF-1R tyrosine phosphorylation, and signaling and synergized with other cytokines to generate macrophages and osteoclasts from cultured progenitors. However, they respectively possessed twofold and fivefold lower affinities for the CSF-1R and correspondingly, lower activities than muCSF-1. Furthermore, muIL-34, when transgenically expressed in a CSF-1-dependent manner in vivo, rescued the bone, osteoclast, tissue macrophage, and fertility defects of Csf1(op)/(op) mice, suggesting similar regulation of CSF-1R-expressing cells by IL-34 and CSF-1. Whole-mount IL34 in situ hybridization and CSF-1 reporter expression revealed that IL34 mRNA was strongly expressed in the embryonic brain at E11.5, prior to the expression of Csf1 mRNA. QRT-PCR revealed that compared with Csf1 mRNA, IL34 mRNA levels were lower in pregnant uterus and in cultured osteoblasts, higher in most regions of the brain and heart, and not compensatorily increased in Csf1(op/op) mouse tissues. Thus, the different spatiotemporal expression of IL-34 and CSF-1 allows for complementary activation of the CSF-1R in developing and adult tissues.

Proliferating SPP1/MERTK-expressing Macrophages in Idiopathic Pulmonary Fibrosis

Abstract: A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis. We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs. IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs. Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.