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Recent studies have demonstrated the existence of a discrete pool of cholesterol in the plasma membranes (PM) of mammalian cells-referred to as the accessible cholesterol pool-that can be detected by the binding of modified versions of bacterial cytolysins (e.g., anthrolysin O). When the amount of accessible cholesterol in the PM exceeds a threshold level, the excess cholesterol moves to the endoplasmic reticulum (ER), where it regulates the SREBP2 pathway and undergoes esterification. We reported previously that the Aster/Gramd1 family of sterol transporters mediates nonvesicular movement of cholesterol from the PM to the ER in multiple mammalian cell types. Here, we investigated the PM pool of accessible cholesterol in cholesterol-loaded fibroblasts with a knockdown of Aster-A and in mouse macrophages from Aster-B and Aster-A/B-deficient mice. Nanoscale secondary ion mass spectrometry (NanoSIMS) analyses revealed expansion of the accessible cholesterol pool in cells lacking Aster expression. The increased accessible cholesterol pool in the PM was accompanied by reduced cholesterol movement to the ER, evidenced by increased expression of SREBP2-regulated genes. Cosedimentation experiments with liposomes revealed that the Aster-B GRAM domain binds to membranes in a cholesterol concentration-dependent manner and that the binding is facilitated by the presence of phosphatidylserine. These studies revealed that the Aster-mediated nonvesicular cholesterol transport pathway controls levels of accessible cholesterol in the PM, as well as the activity of the SREBP pathway.

Macrophages reprogram their lipid metabolism in response to activation signals. However, a systems-level understanding of how different pro-inflammatory stimuli reshape the macrophage lipidome is lacking. Here, we use complementary "shotgun" and isotope tracer mass spectrometry approaches to define the changes in lipid biosynthesis, import, and composition of macrophages induced by various Toll-like receptors (TLRs) and inflammatory cytokines. "Shotgun" lipidomics data revealed that different TLRs and cytokines induce macrophages to acquire distinct lipidomes, indicating their specificity in reshaping lipid composition. Mechanistic studies showed that differential reprogramming of lipid composition is mediated by the opposing effects of MyD88- and TRIF-interferon-signaling pathways. Finally, we applied these insights to show that perturbing reprogramming of lipid composition can enhance inflammation and promote host defense to bacterial challenge. These studies provide a framework for understanding how inflammatory stimuli reprogram lipid composition of macrophages while providing a knowledge platform to exploit differential lipidomics to influence immunity.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Aims: Cognitive frailty can increase the risk of adverse health outcomes in older adults. Estimates of the prevalence of cognitive frailty among older adults with diabetes varied widely in literature. This study aimed to conduct a systematic review and meta‐analysis to assess the pooled prevalence of cognitive frailty and risk factors in community‐dwelling older adults with diabetes, providing evidence for healthcare professionals to better understand the status of cognitive frailty and help develop effective interventions. Methods: Databases of PubMed, Web of Science, Cochrane Library, Embase, Cumulative Index of Nursing and Allied Health, Proquest, China National Knowledge Infrastructure and China Biology Medicine were searched from inception to February 10th, 2022. The reviewers independently selected studies, extracted data and assessed the quality of studies. Pooled prevalence of cognitive frailty and risk factors were estimated. Subgroup analysis, meta‐regression analysis, sensitivity analysis and publication bias were also conducted. Results: A total of 15 studies with 6391 participants were included in this review. The pooled prevalence of cognitive frailty was 11% (95%CI = 7.9–14%) in community‐dwelling older adults with diabetes. Pooled estimates showed that increasing age, higher level of HbA1c, shorter night sleep duration and depression were risk factors, and regular exercise was the protective factor of cognitive frailty in community‐dwelling older adults with diabetes. Conclusion: Cognitive frailty was common in community‐dwelling older adults with diabetes. Routine screening of cognitive frailty and effective interventions should be implemented for this population in community settings. Registration: PROSPERO ID CRD42021276973. [ABSTRACT FROM AUTHOR]