Kancera (Sweden)

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

Abstract In dorsal root ganglia (DRG), macrophages reside in close proximity to sensory neurons, and their functions have largely been explored in the context of pain, nerve injury and repair. In this study, however, we discovered that the majority of macrophages in DRGs are in direct contact with the vasculature where they constantly monitor the circulation, efficiently phagocytosing proteins and macromolecules from the blood. Characterization of the DRG endothelium revealed a specialized vascular network spanning the arteriovenous axis, which gradually transformed from a barrier type endothelium in arteries to a highly permeable endothelium in veins. Macrophage phagocytosis spatially aligned with peak endothelial permeability and we identified caveolar transcytosis as a mechanism regulating endothelial permeability. Profiling of the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover and function. CD163 expressing macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation and were conserved in mouse and Man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.

Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T.cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and invivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.

The sirtuins form a superfamily of evolutionarily conserved NAD(+)-dependent protein N-ϵ-acyl-lysine (AcK) deacylases with roles in a variety of key cellular processes. Sirtuins have a broadly conserved overall structure with a catalytic site formed by a hydrophobic channel between the NAD(+)-binding Rossmann fold domain and a smaller Zn(2+)-binding domain. Schistosomes express five members of the sirtuin family and generic sirtuin inhibitors induce apoptosis and death in schistosome larvae, the disruption of adult worm pairs, inhibition of egg laying and damage to the male and female worm reproductive systems. Sirtuins in schistosomes and other parasitic flatworms present structural differences from their human orthologues that should allow the development of selective inhibitors that can be developed as drug leads.