Inverse data-driven modeling and multiomics analysis reveals Phgdh as a metabolic checkpoint of macrophage polarization and proliferation. Wilson JL, Nagele T, Linke M, Demel F, Fritsch SD, Mayr HK, et al. Serine supports IL-1beta production in macrophages through mTOR signaling.
One-carbon metabolism supports S-adenosylmethionine and histone methylation to drive inflammatory macrophages. Yu W, Wang Z, Zhang K, Chi Z, Xu T, Jiang D, et al. Serine metabolism supports macrophage IL-1beta production. Rodriguez AE, Ducker GS, Billingham LK, Martinez CA, Mainolfi N, Suri V, et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, et al. Regulation of immune responses by L-arginine metabolism. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Rath M, Muller I, Kropf P, Closs EI, Munder M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Stienstra R, Netea-Maier RT, Riksen NP, Joosten LAB, Netea MG. Macrophage immunometabolism: where are we (going)? Trends Immunol. Metabolism supports macrophage activation. Macrophage activation and polarization: nomenclature and experimental guidelines. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al.
Macrophage diversity enhances tumor progression and metastasis. Macrophage plasticity and polarization: in vivo veritas. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation.
Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo.
Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown.
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