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.
Despite the success of current therapies for acute myocardial infarction (MI), many patients still develop adverse cardiac remodeling and heart failure. With the growing prevalence of heart failure, a new therapy is needed that can prevent remodeling and support tissue repair. Herein, we report on injectable recombinant human collagen type I (rHCI) and type III (rHCIII) matrices for treating MI. Injecting rHCI or rHCIII matrices in mice during the late proliferative phase post-MI restores the myocardium’s mechanical properties and reduces scar size, but only the rHCI matrix maintains remote wall thickness and prevents heart enlargement. rHCI treatment increases cardiomyocyte and capillary numbers in the border zone and the presence of pro-wound healing macrophages in the ischemic area, while reducing the overall recruitment of bone marrow monocytes. Our findings show functional recovery post-MI using rHCI by promoting a healing environment, cardiomyocyte survival, and less pathological remodeling of the myocardium.
The maintenance and regulation of the barrier function of the epithelial lining of the intestine are important homeostatic events, serving to allow selective absorption from the gut lumen while simultaneously limiting the access of bacteria into the mucosa. Interferon-gamma is a pleiotrophic cytokine produced predominantly by natural kill cells and CD4+ T cells that under normal circumstances, and particularly during infection or inflammation, will be a component of the intestinal milieu. Use of colon-derived epithelial cell lines and, to a less extent, murine in vivo analyses, have revealed that interferon-gamma (IFN-gamma) can increase epithelial permeability as gauged by markers of paracellular permeability and bacterial transcytosis, with at least a portion of the bacteria using the transcellular permeation pathway. In this review, we describe the main characteristics of epithelial permeability and then focus on the ability of IFN-gamma to increase epithelial permeability, and the mechanism(s) thereof.
Interferon-g (IFNg) is an important immunoregulatory cytokine that can also decrease intestinal epithelial barrier function. Little is known about the intracellular signalling events immediately subsequent to IFNg/IFNg receptor interaction that mediate increases in epithelial permeability; data that could be used to ablate this effect of IFNg while leaving its immunostimulatory effects intact. This study assessed the potential involvement of Src family kinases in IFNg-induced increases in epithelial permeability using confluent filter-grown monolayers of the human colon-derived T84 epithelial cell line. Inhibition of Src kinase with the pharmacologic PP1 and use of Fyn kinase-specific siRNA significantly reduced IFNg-induced increases in epithelial permeability as gauged by translocation of noninvasive E. coli (HB101 strain) and flux of horseradish peroxidase (HRP) across monolayers of T84 cells. However, the drop in transepithelial resistance elicited by IFNg was not affected by either treatment. Immunoblotting revealed that IFNg activated the transcription factor STAT5 in T84 cells, and immunoprecipitation studies identified an IFNg-inducible interaction between STAT5b and the PI3K regulatory subunit p85a through formation of a complex requiring the adaptor molecule Gab2. siRNA targeting STAT5b and Gab2 reduced IFNg-induced increases in epithelial permeability and phosphorylation of PI3K(p85a). PP1 and Fyn siRNA reduced IFNg-induced PI3K activity (indicated by decreased phospho-Akt) and the formation of the STAT5b/PI3K(p85a) complex. Collectively, the results suggest the formation of a Fyn-dependent STAT5b/Gab2/PI3K complex that links IFNg to PI3K signalling and the regulation of macromolecular permeability in a model enteric epithelium.
Oncostatin-M (OSM) is an IL-6/gp130 family member that can stimulate the eosinophil-selective CC chemokine eotaxin-1 in vitro and eosinophil accumulation in mouse lung in vivo. The adhesion molecule VCAM-1 and eotaxin have been implicated in extravasation and accumulation of eosinophils into tissue in animal models of asthma. In this study, we investigated the role of OSM in regulation of VCAM-1 expression, and STAT6 tyrosine 641 phosphorylation in murine fibroblasts. OSM induced VCAM-1 expression in C57BL/6 mouse lung fibroblasts (MLF) and NIH 3T3 fibroblasts at the protein and mRNA level in vitro. OSM also induced STAT6 Y641 phosphorylation in MLF and NIH 3T3 fibroblasts, an activity not observed with other IL-6/gp130 cytokine family members (IL-6, leukemia inhibitory factor, cardiotropin-1, and IL-11) nor in cells derived from STAT6−/− mice (STAT6−/− MLF). STAT6 was not essential for OSM-induced VCAM-1 or eotaxin-1 as assessed in STAT6−/− MLF. Combination of IL-4 and OSM synergistically enhanced eotaxin-1 expression in MLF. IL-4 induction and the IL-4/OSM synergistic induction of eotaxin-1 was abrogated in STAT6−/− MLF, however, regulation of IL-6 was similar in −/− or wild-type MLF. Induction of VCAM-1 by OSM was diminished by pharmacological inhibitors of PI3K (LY294002) but not inhibitors of ERK1/2 (PD98059) or p38 MAPK (SB203580). These data support the role of OSM in eosinophil accumulation into lung tissue through eotaxin-1 and VCAM-1 expression and the notion that OSM is able to induce unique signal transduction events through its receptor complex of OSMR β-chain and gp130.
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