An updated overview of lipid-regulated immunobiology in macrophages

Abstract

Macrophages are well known for their widespread distribution, diverse roles, and involvement in multiple pathophysiological contexts, thereby constructing an immunological front line. Meanwhile, constant efforts over the past few decades have unveiled diverse reprogramming patterns of lipid metabolism as crucial, response- and context-specific drivers of macrophage functions and fate. Here, we take a bird’s-eye view of major fields across the research landscape of lipid-regulated macrophages; review the latest advances in understanding how alterations in several lipid subclasses, especially their fatty acyl composition and oxidative status, direct macrophage-mediated responses and pathology outcomes; and summarize representative insights that have deciphered the lipidome composition of macrophages or profiled specific lipid species under different scenarios. We hope that this review provides readers with a handy grip to learn and explore the field of lipid-regulated immunobiology, exemplified by but not limited to macrophages.

1. Introduction

Initially discovered and named during the 19th century by Ellie Metchnikoff [1], macrophages are among the most prominent and intensively studied myeloid cells in the biomedical literature. They are broadly distributed across various tissues and organs, serve as sentinels to monitor molecular patterns that indicate pathogen invasion or tissue injury, and communicate with adjacent stromal cells or infiltrating leukocytes through cytokines and secretory small molecules, thereby striving to eliminate invaders, organize the extracellular matrix, or maintain tissue homeostasis [2,3]. Given their multifunctional features in different tissues, it is not surprising to observe that they exhibit context-specific heterogeneity. Distinct developmental origins and renewal routes give rise to tissue-resident and monocyte-derived macrophage populations, whereas subtle differences across tissue metabolic milieus further direct macrophages to produce unique patterns of responses [4]. Therefore, how macrophage populations react to extracellular microenvironments and reshape themselves in various ways, ultimately dictating the outcomes of myriad physiological and pathological circumstances, is an intriguing yet important question for researchers.

The metabolic network of lipids has been studied intensively in the past century, comprising a vital piece of the jigsaw puzzle in the field of biochemistry. “Lipids may be broadly defined as small hydrophobic or amphipathic molecules, partly or wholly originated by carbanion-based condensations of thioesters and/or by carbocation-based condensations of isoprene units” according to the LIPID Metabolites And Pathway Strategy (LIPID MAPS®) consortium [5]. From a functional perspective, lipids can serve as reservoirs of energy, as fundamental building blocks of cellular membranes, and as important signal carriers. From an evolutionary perspective, phospholipids assembled in diverse forms play indispensable roles in archaea, bacteria, and eukaryotes [6,7]. Metazoan species, characterized by their multicellularity, further integrate a wider array of lipids (e.g., cholesterol [8]) to reinforce their membrane structure, which enables cells to withstand greater weight and tension, to assemble more complex intracellular structures, and to anchor and cluster proteins that facilitate metabolism, cell movement, and intercellular communication. Given the diversity of lipids and the ever-growing list of newly identified lipids, efforts have been made to better define lipid categories and species with comprehensibility and accuracy. To the best of our knowledge, the lipidome of mammalian cells comprises at least six major lipid categories, including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, and prenol lipids, encompassing thousands of curated lipid species [9] that are distributed across various cellular components or extracellular spaces to execute specialized functions, many of which have not been fully elucidated.