Inflammation by way of macrophage metabolism

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Science  05 May 2017:
Vol. 356, Issue 6337, pp. 488-489
DOI: 10.1126/science.aan2691

Although inflammation is an essential component of immunity, an excessive response can lead to tissue damage and autoimmune pathologies. In most cases, this is avoided with parallel, integrated regulatory responses that allow healing to commence. A central mediator of this regulatory response is the cytokine interleukin-10 (IL-10). IL-10 is particularly important in mucosal tissues, such as the intestine, where it limits macrophage proinflammatory functions. On page 513 of this issue, Ip et al. (1) report that IL-10 alters macrophage function by promoting the clearance of damaged mitochondria and modulating cellular metabolism to limit inflammation.

IL-10 inhibits inflammatory cytokine release from macrophages and the expression of major histocompatibility complex II (which presents antigens to T cells). Individuals bearing mutations in genes encoding IL-10 or the IL-10 receptor (IL-10R) suffer from severe, early onset inflammatory bowel disease. Deletion of either gene in mice leads to spontaneous intestinal inflammation. IL-10R ablation in macrophages alone recapitulates the intestinal inflammation phenotype of global IL-10R deficiency (2).

Macrophage control of inflammation

Release of pro- and anti-inflammatory factors involves mTORC1, mitochondria, and metabolic processes.


Metabolic reprogramming occurs in response to changes in nutrient or oxygen availability. In immune cells, such reprogramming is also regulated by ligation of receptors for pathogen-associated molecular patterns [e.g., Toll-like receptors (TLRs)] or damage-associated molecular patterns, antigens, and certain cytokines. Metabolic reprogramming also influences cellular fate and function and, consequently, immune response outcome.

When exposed to the TLR4 ligand bacterial lipopolysaccharide (LPS), macrophages produce proinflammatory cytokines and engage aerobic glycolysis to generate adenosine triphosphate (ATP) independently of mitochondrial oxidative phosphorylation (OXPHOS) (3, 4). Ip et al. observed that macrophages from mice lacking IL-10 exhibited increased glycolysis in response to LPS. By contrast, OXPHOS was decreased. This is consistent with the effect of IL-10 on dendritic cells—minimizing the LPS-induced shift to glycolytic metabolism, which ultimately inhibits cell activation (3).

After stimulation with LPS, IL-10-null macrophages had low cellular ATP and accumulated damaged mitochondria due to a failure of mitophagy, a process that targets mitochondria for autophagic recycling. Damaged mitochondria generate increased amounts of reactive oxygen species (ROS), a product of OXPHOS, which can be damaging. Previous findings implicated ROS (made by complex I of the electron transfer chain) in the activation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) and in downstream events, including proinflammatory IL-1β production (5). Overall, the findings of Ip et al. are consistent with impaired mitophagy in skeletal muscle in IL-10-deficient mice (6), but contrast with studies that associate IL-10 with blocking autophagy (7). This disparity may reflect distinct events in mitophagy compared to starvation-induced autophagy that are regulated by IL-10. Upstream events linked to mitochondrial fission, which is necessary for mitophagy to proceed, or proteins that target mitochondria for mitophagy, may be important in this context.

Many signals that control autophagy converge on mammalian target of rapamycin complex 1 (mTORC1), a signaling hub that regulates anabolic pathways such as glycolysis. Inhibition of mTORC1 promotes catabolism through processes including autophagy. Indeed, Ip et al. found that lack of IL-10 signaling in LPS-treated macrophages resulted in sustained mTORC1 activation, which would explain decreased mitophagy. The inhibitory effect of IL-10 on mTORC1 required signal transducer and activator of transcription 3 (STAT3) and could be recapitulated by addition of the mTORC1 inhibitor rapamycin. IL-10 has not previously been considered to mediate its effects by inhibiting mTORC1 activity in myeloid cells.

To find out how IL-10 controls mTORC1 signaling, Ip et al. analyzed the expression of genes encoding known negative regulators of the mTORC1 pathway. The authors identified the expression of DNA-damage-inducible transcript 4 protein (DDIT4) in a STAT3-dependent manner early after LPS treatment in macrophages, only when IL-10 was present. Loss of DDIT4 in macrophages recapitulated key features of IL-10 deficiency, including increased mTORC1 activation, glycolysis, and the accumulation of damaged mitochondria after LPS treatment. IL-10 did not suppress mTORC1 activation or glycolysis in LPS-stimulated DDIT4-null cells, but interestingly, it rescued the decline in OXPHOS. Thus, much of the metabolic change observed in IL-10-null macrophages is due to a failure to both induce DDIT4 expression and block mTORC1. Moreover, macrophages isolated from patients with mutations in the IL-10R showed prolonged mTORC1 activation, decreased DDIT4 expression, and increased IL-1β secretion after LPS stimulation, indicating that IL-10 also engages the DDIT4-mTORC1 pathway in inflammatory human macrophages.

Implicated in autophagy in chondrocytes (8), DDIT4 is also involved in mTORC1 inhibition in the context of hypoxia (9). It also inhibits mTORC1 activation and glycolysis in hypoxic tumor-associated macrophages (10). Intriguingly, in hypoxia, DDIT4 transcription is induced by HIF-1α (11), but Ip et al. allude that IL-10-induced expression of this factor is HIF-1α-independent. Therefore, it is possible that pathways such as hypoxia that normally regulate DDIT4 expression in macrophages (and other cells) are rewired to become controlled by IL-10 and STAT3 after LPS stimulation.

The findings of Ip et al., suggest that through induced mitophagy, IL-10 reduces LPS-induced IL-1β production by preventing excessive ROS release from complex II in damaged mitochondria and limiting inflammasome activation (see the figure). However, IL-10 also decreases expression of inflammasome components (12), suggesting that there may be overlapping mechanisms of IL-10-driven inflammasome inhibition.

Does IL-10 have the same effect on other immune cell types? For example, does it support regulatory T (Treg) cell development by inhibiting mTORC1 activation? It seems plausible because mTORC1 inhibition promotes Treg cell differentiation (13) and because mTORC1 activity is modulated in Treg cells upon TLR activation (14). Moreover, decreased autophagy suppresses Treg cell responses, particularly within the intestinal mucosa (15). A role for DDIT4 in Treg cells will be interesting to explore.


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