Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.

Macrophages are plastic cells playing a crucial role in innate immunity. While fundamental in responding to infections, when persistently maintained in a pro-inflammatory state they can initiate and sustain inflammatory diseases. Therefore, a strategy that reprograms pro-inflammatory macrophages toward an anti-inflammatory phenotype could hold therapeutic potential in that context. We have recently shown that arginase 2 (Arg2), a mitochondrial enzyme involved in arginine metabolism, promotes the resolution of inflammation in macrophages and it is targeted by miR-155. Here, we designed and tested a target site blocker (TSB) that specifically interferes and blocks the interaction between miR-155 and Arg2 mRNA, leading to Arg2 increased expression and activity. In bone marrow-derived macrophages transfected with Arg2 TSB (in the presence or absence of the pro-inflammatory stimulus LPS), we observed an overall shift of the polarization status of macrophages toward an anti-inflammatory phenotype, as shown by significant changes in surface markers (CD80 and CD71), metabolic parameters (mitochondrial oxidative phosphorylation) and cytokines secretion (IL-1ß, IL-6, and TNF). Moreover, in an in vivo model of LPS-induced acute inflammation, intraperitoneal administration of Arg2 TSB led to an overall decrease in systemic levels of pro-inflammatory cytokines. Overall, this proof-of-concept strategy represent a promising approach to modulating macrophage phenotype.

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

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-1ß in vitro. Accordingly, HIF-1α and IL-1ß 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.

Nanomodulation of Macrophages in Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic demyelinating autoimmune disease primarily affecting young adults. Despite an unclear causal factor, symptoms and pathology arise from the infiltration of peripheral immune cells across the blood brain barrier. Accounting for the largest fraction of this infiltrate, macrophages are functionally heterogeneous innate immune cells capable of adopting either a pro or an anti-inflammatory phenotype, a phenomenon dependent upon cytokine milieu in the CNS. This functional plasticity is of key relevance in MS, where the pro-inflammatory state dominates the early stage, instructing demyelination and axonal loss while the later anti-inflammatory state holds a key role in promoting tissue repair and regeneration in later remission. This review highlights a potential therapeutic benefit of modulating macrophage polarisation to harness the anti-inflammatory and reparative state in MS. Here, we outline the role of macrophages in MS and look at the role of current FDA approved therapeutics in macrophage polarisation. Moreover, we explore the potential of particulate carriers as a novel strategy to manipulate polarisation states in macrophages, whilst examining how optimising macrophage uptake via nanoparticle size and functionalisation could offer a novel therapeutic approach for MS.