Differentiated macrophages acquire a pro-inflammatory and cell death-resistant phenotype due to increasing XIAP and p38-mediated inhibition of RipK1.

Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations, and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that specifically depended on tumor necrosis factor α (TNFα) expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)-RipK3-caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of pro-inflammatory cytokines but reduced RipK1-dependent cell death and the RipK3-caspase-8 interaction. The expression of the anti-apoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIPL), also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogen-activated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/MK2 pathway overrides apoptosis inhibition by XIAP and that acquisition of resistance to cell death by increased expression of XIAP and cFLIPL may allow inflammatory macrophages to participate in pathogen control for a longer duration.

Cardiac CT assessment of left ventricular mass in mid-diastasis and its prognostic value.

AIMS: To determine the influence of cardiac motion on measurements of left ventricular (LV) mass obtained with 64-slice computed tomography (CT) and to elucidate the prognostic value of LV mass on major adverse cardiac events (MACE) and all-cause mortality. Increased LV mass has been linked with MACE. Although Cardiac CT allows measurement of LV anatomy, it is susceptible to motion artefacts often requiring image acquisition during diastasis. There is a need to understand variability in LV mass measurements across phases of the cardiac cycle, and whether mid-diastolic measurements have prognostic value. METHODS AND RESULTS: The study comprised two equally sized cohorts of patients that had undergone retrospectively gated cardiac CT: patients who had MACE and/or all-cause death at follow-up and a matched (age, sex, and risk factors) event-free cohort. LV mass was measured at mid-diastole, end-diastole, and end-systole. Correlation and agreement between phases were determined. The incremental value of mid-diastolic hypertrophy (LVH) over the National Cholesterol Education Programme (NCEP) risk was performed for LV mass indices normalized to body surface area (LVMIBSA) or weight (LVMIWeight). Of 166 patients, 31.3% experienced MACE and 28.9% died of any cause (follow-up 22.9 ± 13.4 months). LV mass at all cardiac phases were strongly correlated (r > 0.94). Mean mid-diastolic LVMIBSA was higher in the cohort with events (93.7 vs. 80.7 g/m2, P= 0.008) as was LVMIWeight (2.26 vs. 1.88 g/kg, P = 0.001). LVMIBSA and LVMIWeight had prognostic value incremental to NCEP with 1.85 and 2.47 hazard ratios, respectively. CONCLUSIONS: Measurement of LV mass can be obtained by cardiac CT images obtained at mid-diastasis. LV mass measurements obtained at mid-diastasis have prognostic value.

Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8(+) T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria.