Fig. 3: The metabolic reprogramming of activated ILC2s in humans and mice.

a IL-33-activated human ILC2s rely on OXPHOS to sustain fitness and proliferation, whereas IL-13 production is dependent on glycolysis and the mTOR pathway. b In mice, activated ILC2s rely primarily on FAO (green dashed region) and amino acid metabolism. FFAs are acquired externally through CD36 (1) and are temporarily stored as lipid droplets, which are regulated by Atg5-dependent autophagy (2) and DGAT1 (3). PPAR-γ regulates lipid uptake by promoting CD36 and DGAT1 expression, whereas its expression is regulated by glucose/mTOR signaling (4). Fatty acids stored as lipid droplets are further used to fuel FAO or converted into phospholipids to promote ILC2 proliferation. PLA2G5-expressing macrophages are important sources of FFAs (namely, linoleic acid and oleic acid) under inflammatory conditions (5). Moreover, PLA2G5 intrinsically regulates GPR40 receptor expression on ILC2s, and activation of this receptor by FFAs, particularly linoleic acid, promotes ILC2 expansion through an undefined mechanism (6). Amino acids such as methionine and arginine play crucial yet distinct roles in ILC2 functions. Methionine metabolism (brown dashed region) epigenetically regulates Il13 and Il5 by producing the methyl-donating substrate SAM through a STAT3-dependent mechanism (7). In contrast, Arg1 metabolizes arginine to fuel polyamine biosynthesis (blue dashed region), which supports glycolysis (8). Functional fine-tuning of glycolysis (purple dashed region) is important to limit ILC2 functions. PD-1 is an important metabolic checkpoint that keeps glycolysis in check, and PD-1-deficient ILC2s exhibit increased glycolysis and aberrant functions (9). Moreover, the PKM2/pyruvate checkpoint, which negatively regulates Il1rl1 (which encodes ST2) expression by suppressing H3K4me3, is kept in check by the E3 ubiquitin ligase VHL through HIF-1α degradation (10). The effects of VHL are denoted in orange. The full term for each abbreviation can be found in the text.