A Mitochondrial Polymorphism Alters Immune Cell Metabolism and Protects Mice from Skin Inflammation.

Several genetic variants in the mitochondrial genome (mtDNA), including ancient polymorphisms, are associated with chronic inflammatory conditions, but investigating the functional consequences of such mtDNA polymorphisms in humans is challenging due to the influence of many other polymorphisms in both mtDNA and the nuclear genome (nDNA). Here, using the conplastic mouse strain B6-mtFVB, we show that in mice, a maternally inherited natural mutation (m.7778G > T) in the mitochondrially encoded gene ATP synthase 8 (mt-Atp8) of complex V impacts on the cellular metabolic profile and effector functions of CD4+ T cells and induces mild changes in oxidative phosphorylation (OXPHOS) complex activities. These changes culminated in significantly lower disease susceptibility in two models of inflammatory skin disease. Our findings provide experimental evidence that a natural variation in mtDNA influences chronic inflammatory conditions through alterations in cellular metabolism and the systemic metabolic profile without causing major dysfunction in the OXPHOS system.

12/15-Lipoxygenase choreographs the resolution of IgG-mediated skin inflammation.

Autoimmune diseases are defined by an immune response against a specific autoantigen, driven by antigen-specific T cells or antibodies. While the mechanisms resolving brief episodes of acute inflammation elicited by microbial components or tissue injury are well understood, the mechanisms resolving tissue inflammation in autoimmune diseases are still largely elusive. We have, therefore, addressed the mechanisms of resolution in IgG-mediated autoimmune diseases using a mouse model of the pemphigoid disease "bullous pemphigoid-like epidermolysis bullosa acquisita" (BP-like EBA) as prototypical example. We found that 12/15-LO is induced in skin lesions of BP-like EBA and is predominantly expressed in eosinophils. Dependent on the expression of 12/15-LO, large amounts of proresolving lipid mediators, are biosynthesized in the skin by the point disease peaks. Their production is timely correlated to the gradual reversal of tissue inflammation. Genetic deficiency in Alox15, the gene encoding 12/15-LO, disrupts this process significantly protracting and aggravating disease. This protraction is associated reduced recruitment of regulatory T cells (Tregs) into lesional skin. Intriguingly, Alox15-/- mice also exhibit reduced recruitment of eosinophils into the skin, and the chemotaxis of cultured Alox15-/- eosinophils towards CCL11/eotaxin-1 is compromised. Finally, we demonstrate that 15-lipoxygenase-1, the human homologue of 12/15-LO is induced in granulocytes in lesional skin of patients suffering from a pemphigoid disease. Collectively, our result uncover key mechanisms resolving IgG-mediated skin inflammation. These mechanisms are orchestrated by 12/15-LO expressed in eosinophils promoting the recruitment of eosinophils and Tregs, which in turn inhibit neutrophils.

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease.

The treatment of most autoimmune diseases still relies on systemic immunosuppression and is associated with severe side effects. The development of drugs that more specifically abrogate pathogenic pathways is therefore most desirable. In nature, such specificity is exemplified, e.g., by the soft tick-derived biotherapeutic Coversin, which locally suppresses immune responses by inhibiting complement factor 5 (C5) and leukotriene B4 (LTB4). C5a, a proteolytic fragment of C5, and LTB4 are critical drivers of skin inflammation in pemphigoid diseases (PDs), a group of autoimmune blistering skin diseases. Here, we demonstrate that both Coversin and its mutated form L-Coversin, which inhibits LTB4 only, dose dependently attenuate disease in a model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA). Coversin, however, reduces disease more effectively than L-Coversin, indicating that inhibition of C5 and LTB4 synergize in their suppressing effects in this model. Further supporting the therapeutic potential of Coversin in humans, we found that C5a and LTB4 are both present in the blister fluid of patients with BP in quantities inducing the recruitment of granulocytes and that the number of cells expressing their receptors, C5aR1 and BLT1, respectively, is increased in perilesional skin. Collectively, our results highlight Coversin and possibly L-Coversin as potential therapeutics for PDs.