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.

Type I IFN signalling is required for cationic adjuvant formulation (CAF)01-induced cellular immunity and mucosal priming.

Despite being in the midst of a global pandemic of infections caused by the pathogen Chlamydia trachomatis, a vaccine capable of inducing protective immunity remains elusive. Given the C. trachomatis mucosal port of entry, a formulation compatible with mucosal administration and capable of eliciting potent genital tract immunity is highly desirable. While subunit vaccines are considered safer and better tolerated, these are typically poorly immunogenic and require co-formulation with immune-potentiating adjuvants. However, of the adjuvants licensed for use in humans, very few drive robust cellular responses, a pre-requisite for protection against C. trachomatis infection. Recently, the cationic adjuvant formulations (CAF) have been shown to induce robust humoral and cellular immunity in pre-clinical models of chlamydia, malaria and tuberculosis (TB). Here, we demonstrate that CAF01 induces potent immune responses when combined with the major outer membrane protein (MOMP) of C. trachomatis following parenteral immunisation and also as part of a heterologous prime/boost regime. We show that a subcutaneous prime with CAF01-adjuvanted recombinant MOMP licenses antigen-specific immunity at distant mucosal sites which can be activated following oral antigen re-encounter in the absence of concomitant adjuvant stimulation. Finally, we shed light on the mechanism(s) through which CAF01 elicits robust antigen-specific immunity to co-formulated MOMP via type I interferon (IFN) signalling.

Modulation of innate immunity by cyclosporine A.

Cyclosporine A has long been known to suppress T cell responses by inhibiting the production of IL-2, which drives T cell proliferation, enabling its use as a therapeutic for transplantation or autoimmunity. However, cyclosporine A also impacts on innate immune cells including dendritic cells, macrophages and neutrophils. In dendritic cells, which are essential for T cell priming, cyclosporine A can modulate both expression of surface molecules that engage with T cells and cytokine secretion, leading to altered induction of T cell responses. In macrophages and neutrophils, which play key antimicrobial roles, cyclosporine A reduces the production of cytokines that can play protective roles against pathogens. Some of these molecules, if produced in the context of chronic disease, can also contribute to pathology. There have been a number of elegant recent studies addressing the mechanisms by which cyclosporine A can modulate innate immunity. In particular, cyclosporine A inhibits the release of mitochondrial factors that stimulate the production of type 1 interferons by innate immune cells. This review addresses the emerging literature on modulation of innate immune responses by cyclosporine A, its resultant impact on adaptive immune responses and how this offers potential for new therapeutic applications.