Integration of transcriptional and metabolic control in macrophage activation

Abstract

Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus‐specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal‐induced metabolic changes and gene expression is still lacking. Here, we discuss current evidence, controversies, knowledge gaps, and future areas of investigation on how metabolic and transcriptional changes are dynamically integrated during macrophage activation. The cross‐talk between metabolism and inflammatory gene expression is in part accounted for by alterations in the production, usage, and availability of metabolic intermediates that impact the macrophage epigenome. In addition, stimulus‐inducible gene expression changes alter the production of inflammatory mediators, such as nitric oxide, that in turn modulate the activity of metabolic enzymes thus determining complex regulatory loops. Critical issues remain to be understood, notably whether and how metabolic rewiring can bring about gene‐specific (as opposed to global) expression changes.

3-OH Phloretin Inhibits High-Fat Diet-Induced Obesity and Obesity-Induced Inflammation by Reducing Macrophage Infiltration into White Adipose Tissue

“…Obesity induces upregulated expression of chemokines such as MCP-1 (monocyte chemoattractant protein-1, CCL2) and CCL5 (C-C Motif Chemokine Ligand 5) in order to recruit M1 macrophages to adipose tissues [ 39 ]. These recruited M1 macrophages secrete pro-inflammatory cytokines, including TNF, IL-6, and IL-1β, and oxidative metabolites such as superoxide and nitric oxide (NO), resulting in inflammation and insulin resistance [ 40 , 41 ]. Increased pro-inflammatory cytokines, oxidative stress, and insulin resistance promote the progression of obesity, and obesity also induces inflammation and insulin resistance [ 42 ].…”

Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury

“…Macrophages mediate the immune response by recognizing substances, such as danger signaling molecules, fatty acids, cellular debris, and ROS [ 53 , 54 , 55 ]. Macrophage activation is mainly achieved through recognition of surface pattern recognition receptors, including TLRs [ 56 ].…”

High aspect ratio nanomaterial-induced macrophage polarization is mediated by changes in miRNA levels

“…CNF and NM-401 were selected based on their observed ability to enhance M1 polarization (CNF) and M2 polarization (NM-401). The confirmed rRNA modifications (50): m 1 A, m 6 A, m 6,6 A, m 5 C, ac 4 C, m 7 G, m 2 G, Y, m 3 U, and the 2'-O-Me (Am, Cm, Gm, and Um) were analyzed. Exposure to CNF and NM-401 did not induce changes in the analyzed rRNA modifications, Supplementary Table 4.…”

“…Albeit various nanomaterials have been shown to possess immunomodulating properties, the involvement of macrophage polarization in nanomaterial-induced pulmonary inflammation and fibrosis is not well understood. The transition of macrophage phenotypes is tightly controlled by transcriptional and metabolic changes and is fine-tuned by epigenetic regulation (1,4,5). The epigenetic regulation occurs through histone modifications (e.g., methylation and acetylation mostly at lysine residues), DNA (5mC) and RNA modifications (e.g., m6A, m5C, m1A, 2'-O-Me, and Y), and non-coding RNAs.…”