Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals

Abstract

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…Mechanistically, this involves the ability of mTORC1 to promote the effects of Akt on ATP-citrate lyase (Acly), thereby affecting gene-specific histone acetylation and the regulation of expression of a subset of genes that mark the alternatively activated state (Covarrubias et al, 2015). Consistent with this, in separate studies, Lamtor1 (a key component of the amino acid-sensing machinery), is found to play an essential role in the ability of macrophages to become alternatively activated in response to IL-4 (Kimura et al, 2016). …”

Myeloid Folliculin balances mTOR activation to maintain innate immunity homeostasis

“…BMDMs lacking FLCN are hypersensitive to LPS and CpG stimuli. LPS-mediated activation of canonical mTORC1 has been implicated in macrophage inflammatory response (25,26), and TFE3 and TFEB have recently been shown to drive mRNA expression of inflammatory genes in macrophages (23). We therefore reasoned that cells lacking FLCN, in which both of these pathways are activated, may be partially activated, even in absence of inflammatory stimulation, and/or may be hypersensitive to inflammatory signals.…”

Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase

“…Thus, the lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with V-ATPase, was recently shown to be required for M2 polarization [55]. Moreover, V-ATPase was reported to modulate macrophage polarization in tumor-bearing mice [56], and inhibition of the V-ATPase a2 isoform in murine tumor cells delayed tumor growth by decreasing M2-like TAMs in the tumor microenvironment [57].…”