Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Abstract

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

“…Among these cytokines is interleukin-10 (IL-10), a potent anti-inflammatory signalling molecule that in the brain, for example, modulates astroglial activation and neuroinflammation [ 185 ]. In macrophages, IL-10 has been shown to directly regulate mitochondrial dynamics and respiration via mitochondrial arginase-2 [ 186 ]. Neuroprotective IL-10 effects are therefore likely partially mediated by the metabolic reprogramming of mitochondria.…”

Endothelial arginase 2 mediates retinal ischemia/reperfusion injury by inducing mitochondrial dysfunction

“…Though further work is required to define the role of A2 in normal mitochondrial function, our study is the first to show a potential involvement of A2 upregulation in promoting mitochondrial fission and dysfunction in endothelial cells. Interestingly, a very recent study found that A2 is involved in IL-10 mediated mitochondrial fusion in macrophages, suggesting the different effects of A2 on the mitochondrial dynamics in different cell types [ 50 ]. Here we showed that A2 overexpression induces mitochondrial dysfunction in normoxic conditions, as demonstrated by the reduction of basal respiration, maximal respiration, ATP production, and spare respiratory capacity.…”

“…Live cell images were taken using a Zeiss LSM 780 Inverted Confocal microscopy (Carl Zeiss AG, Oberkochen, Germany) with a 63x lens. Four random images per dish were taken, and the numbers of cells with fragmented mitochondria were counted and divided by the total number of cells per image to get the fraction of cells with fragmented mitochondria [ 50 ]. Averages of the four images from each data set were calculated to represent an individual data point in the final graph.…”

Adjuvant and immunomodulatory potential ofin vivoNatural Killer T (NKT) activation by NKTT320

“…As illustrated in the schematic (Figure 10), side-by-side with activation, NKTT320 triggered several genes encoding markers of resolution of inflammation. Most prominent of the upregulated genes included the inflammation resolution genes NLRP12 and CMKLR1 (Fullerton and Gilroy, 2016, Ohira et al, 2010), the metabolic regulator ARG-2 (Dowling et al, 2021), and the inhibitory receptors FCGR2B and PD-L1 (Nimmerjahn and Ravetch, 2008, Freeman et al, 2000). In all, the concordant immune activation and anti-inflammatory responses induced by NKTT320 may mean that there is a potential in vivo for eliciting potent inflammatory responses without excessive or non-resolving immune activation.…”