The transcriptional control of the VEGFA-VEGFR1 (FLT1) axis in alternatively polarized murine and human macrophages

Introduction: Macrophages significantly contribute to the regulation of vessel formation under physiological and pathological conditions. Although the angiogenesis-regulating role of alternatively polarized macrophages is quite controversial, a growing number of evidence shows that they can participate in the later phases of angiogenesis, including vessel sprouting and remodeling or regression. However, the epigenetic and transcriptional regulatory mechanisms controlling this angiogenesis-modulating program are not fully understood. Results: Here we show that IL-4 can coordinately regulate the VEGFA-VEGFR1 (FLT1) axis via simultaneously inhibiting the proangiogenic Vegfa and inducing the antiangiogenic Flt1 expression in murine bone marrow-derived macrophages, which leads to the attenuated proangiogenic activity of alternatively polarized macrophages. The IL-4-activated STAT6 and IL-4-STAT6 signaling pathway-induced EGR2 transcription factors play a direct role in the transcriptional regulation of the Vegfa-Flt1 axis. We demonstrated that this phenomenon is not restricted to the murine bone marrow-derived macrophages, but can also be observed in different murine tissue-resident macrophages ex vivo and parasites-elicited macrophages in vivo with minor cell type-specific differences. Furthermore, IL-4 exposure can modulate the hypoxic response of genes in both murine and human macrophages leading to a blunted Vegfa/VEGFA and synergistically induced Flt1/FLT1 expression. Discussion: Our findings establish that the IL-4-activated epigenetic and transcriptional program can determine angiogenesis-regulating properties in alternatively polarized macrophages under normoxic and hypoxic conditions

The experience of Community Programme, unemployment and employment : mental health and individual differences.

This thesis explores some theoretical, conceptual, empirical and methodological issues concerning psychological research into unemployment. A review of the literature revealed some important limitations in the approach which has hitherto been taken to examine this phenomenon. Specific weaknesses included an undervaluation of the role of theory, a dearth of empirical research on intervention programmes or other responses to unemployment, as well as oversimplification, overgeneralisation, imprecision and unfalsifiability in the theoretical contributions which have been offered. Moreover, it was noted that there had been a lack of attention to dispositional factors in empirical research or theory, and inadequate (particularly undifferentiated) conceptualisation and operationalisation of mental health variables. The empirical part of the study, therefore, was developed as an initial exploration of (a) Individual differences in the mental health of unemployed adults, and (b) the experience of participation on Community Programme (CP), a UK government intervention for long-term unemployed adults. A multi-method, multivariate design was used adopting a theoretically grounded, guiding conceptual framework. Qualitative in-depth interviews (N = 60) were conducted with CP participants from two CP managing agencies. In addition, a large scale cross-sectional quantitative survey (N=484) was undertaken incorporating individuals who were: (a) Participating on CP (b) Employed (c) Unemployed. The findings of the stud demonstrated a number of relationships between personal characteristics (i. e. demographic and personality related variables), intervening variables and dimensions of mental health. Some theoretical and empirical implications of these findings were discussed and directions for future empirical research and theoretical development were suggested. With respect to the experience of Community Programme, the findings suggested that within these two managing agencies, the content of the scheme (i. e. the nature of the work) was evaluated positively by the respondents, but that the context of the scheme and its temporary nature were perceived in a negative light. Some suggestions are made as to how these different aspects of the scheme impacted upon the mental health of the participants

Macrophage and epithelial cell H-ferritin expression regulates renal inflammation

Inflammation culminating in fibrosis contributes to progressive kidney disease. Cross-talk between the tubular epithelium and interstitial cells regulates inflammation by a coordinated release of cytokines and chemokines. Here we studied the role of heme oxygenase-1 (HO-1) and the heavy subunit of ferritin (FtH) in macrophage polarization and renal inflammation. Deficiency in HO-1 was associated with increased FtH expression, accumulation of macrophages with a dysregulated polarization profile, and increased fibrosis following unilateral ureteral obstruction in mice: a model of renal inflammation and fibrosis. Macrophage polarization in vitro was predominantly dependent on FtH expression in isolated bone marrow-derived mouse monocytes. Using transgenic mice with conditional deletion of FtH in the proximal tubules (FtH(PT-/-)) or myeloid cells (FtH(LysM-/-)), we found that myeloid FtH deficiency did not affect polarization or accumulation of macrophages in the injured kidney compared with wild-type (FtH(+/+)) controls. However, tubular FtH deletion led to a marked increase in proinflammatory macrophages. Furthermore, injured kidneys from FtH(PT-/-) mice expressed significantly higher levels of inflammatory chemokines and fibrosis compared with kidneys from FtH(+/+) and FtH(LysM-/-) mice. Thus, there are differential effects of FtH in macrophages and epithelial cells, which underscore the critical role of FtH in tubular-macrophage cross-talk during kidney injury

Pharmacological induction of ferritin prevents osteoblastic transformation of smooth muscle cells

Vascular calcification is a frequent complication of atherosclerosis, diabetes, and chronic kidney disease. In the latter group of patients, calcification is commonly seen in tunica media where smooth muscle cells (SMC) undergo osteoblastic transformation. Risk factors such as elevated phosphorus levels and vitamin D3 analogs have been identified. Inlight of earlier observations by our group and others, we sought to inhibit SMC calcification via induction of ferritin. Human aortic SMC were cultured using β-glycerophosphate with activated vitamin D3, or inorganic phosphate with calcium, and induction of alkaline phosphatase and osteocalcin as well as accumulation of calcium were used to monitor osteoblastic transformation. Additionally, to examine the role of vitamin D3 analogs, plasma samples from patients on hemodialysis who hadreceived calcitriol or paricalcitol were tested for their tendency to induce calcification of SMC. Addition of exogenous ferritin mitigates the transformation of SMC into osteoblast-like cells. Importantly, pharmacologic induction of heavy chain ferritin by 3H-1,2-Dithiole-3-thione was able to inhibit the SMC transition into osteoblast-like cells and calcification of extracellular matrix. Plasma samples collected from patients after administration of activated vitamin D3 caused significantly increased alkaline phosphatase activity in SMC compared to samples drawn prior to activated vitamin D3 and here, again induction of ferritin diminished the osteoblastic transformation. Our data suggests that pharmacologic induction of ferritin prevents osteoblastic transformation of SMC. Hence, utilization of such agents thatwill cause enhanced ferritin synthesis may have important clinical application in prevention of vascular calcification