Reprogramming cholesterol metabolism in macrophages and its role in host defense against cholesterol-dependent cytolysins

Steven J. Bensinger,Min-Sub Lee

doi:10.1038/s41423-021-00827-0

Steven J. Bensinger, Min-Sub Lee

Open Access

https://doi.org/10.1038/s41423-021-00827-0

Copy DOI

Abstract

Cholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.

Highlights

Macrophages are key players in the innate immune system and are tasked with responding to a diverse array of pathogens
Macrophages rely on recognizing pathogen-associated molecular patterns (PAMPs) through the engagement of pattern-recognition receptors (PRRs) and other similar receptors [1, 2]
This review focuses on one interesting and less understood aspect of metabolic reprogramming: the abrupt and profound shift in cellular cholesterol homeostasis induced by PRR signals and other proinflammatory stimuli

Summary

REVIEW ARTICLE

Cholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. The mechanism by which IFN-induced changes in the accessible cholesterol pool alter CDC sensitivity may only be relevant to the plasma membrane., this study reinforces the growing concept that reprogramming the pool of accessible plasma membrane cholesterol with IFNs can protect cells from damage induced by microbes Based on these new concepts in membrane cholesterol homeostasis, it will be interesting to revisit whether other intracellular microbes that exploit cellular cholesterol for their determine the extent to which activation signals reshape lipid lifecycle depend on the accessible cholesterol pool. It will be exciting for the field to generate comprehensive pathogen-based immune metabolic studies to guide our thinking and shape models

Another series of questions for the field to address center

Findings

ADDITIONAL INFORMATION