Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD⁺/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.

Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs. Both tumor cells and macrophages undergo metabolic reprogramming to meet energy demands in the TME. Understanding the metabolic rewiring in TAMs can shed light on immune escape mechanisms and provide insights into repolarizing TAMs towards anti-tumorigenic function. Here, we discuss how metabolism impinges on the functional divergence of macrophages and its relevance to macrophage polarization in the TME.

During differentiation and development, cell fate and identity are established by waves of genetic reprogramming. Although the mechanisms are largely unknown, during these events, dynamic chromatin reorganization is likely to ensure that multiple genes involved in the same cellular functions are coregulated, depending on the nuclear environment. In this study, using high‐content screening of embryonic fibroblasts from a β‐actin knockout (KO) mouse, we found major chromatin rearrangements and changes in histone modifications, such as methylated histone (H)3‐lysine‐(K)9. Genome‐wide H3K9 trimethylation‐(Me)3 landscape changes correlate with gene up‐ and down‐regulation in β‐actin KO cells. Mechanistically, we found loss of chromatin association by the Brahma‐related gene ( Brg )/Brahma‐associated factor (BAF) chromatin remodeling complex subunit Brgl in the absence of β‐actin. This actin‐dependent chromatin reorganization was concomitant with the up‐regulation of sets of genes involved in angiogenesis, cytoskeletal organization, and myofibroblast features in β‐actin KO cells. Some of these genes and phenotypes were gained in a β‐actin dose‐dependent manner. Moreover, reintroducing a nuclear localization signal‐containing β‐actin in the knockout cells affected nuclear features and gene expression. Our results suggest that, by affecting the genome‐wide organization of heterochromatin through the chromatin‐binding activity of the BAF complex, β‐actin plays an essential role in the determination of gene expression programs and cellular identity.—Xie, X., Almuzzaini, B., Drou, N., Kremb, S., Yousif, A., Östlund Farrants, A.‐K., Gunsalus, K., Percipalle, P. β‐Actin‐dependent global chromatin organization and gene expression programs control cellular identity. FASEB J. 32,1296‐1314 (2018). www.fasebj.org