CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions

Pu Ste Liu, Yi Ting Chen, Xiaoyun Li, Pei Chun Hsueh, Sheue Fen Tzeng, Hsi Chen, Pei Zhu Shi, Xin Xie, Sweta Parik, Mélanie Planque, Sarah Maria Fendt, Ping Chih Ho

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)452-462
Number of pages11
JournalNature Immunology
Volume24
Issue number3
DOIs
Publication statusPublished - 2023 Mar

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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