Disruption of Cxcr3 chemotactic signaling alters lysosomal function and renders macrophages more microbicidal.

Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome physiology in macrophages during mycobacterial infection and wound-induced inflammation in vivo. Macrophages from zebrafish larvae carrying a mutation in a chemokine receptor of the Cxcr3 family display upregulated expression of vesicle trafficking and lysosomal genes and possess enlarged lysosomes that enhance intracellular bacterial clearance.

A quantitative in vivo assay for craniofacial developmental toxicity of histone deacetylases.

Many bony features of the face develop from endochondral ossification of preexisting collagen-rich cartilage structures. The proper development of these cartilage structures is essential to the morphological formation of the face. The developmental programs governing the formation of the pre-bone facial cartilages are sensitive to chemical compounds that disturb histone acetylation patterns and chromatin structure.

Inhibition of macrophage migration in zebrafish larvae demonstrates in vivo efficacy of human CCR2 inhibitors.

The chemokine signaling axes CCR2-CCL2 and CXCR3-CXCL11 participate in the inflammatory response by recruiting leukocytes to damaged tissue or sites of infection and are, therefore, potential pharmacological targets to treat inflammatory disorders. Although multiple CCR2 orthosteric and allosteric inhibitors have been developed, none of these compounds has been approved for clinical use, highlighting the need for a fast, simple and robust preclinical test system to determine the in vivo efficacy of CCR2 inhibitors. Herein we show that human CCL2 and CXCL11 drive macrophage recruitment in zebrafish larvae and that CCR2 inhibitors designed for humans also limit macrophage recruitment in this model organism due to the high conservation of the chemokine system.

Modeling Infectious Diseases in the Context of a Developing Immune System.

Zebrafish has been used for over a decade to study the mechanisms of a wide variety of inflammatory disorders and infections, with models ranging from bacterial, viral, to fungal pathogens. Zebrafish has been especially relevant to study the differentiation, specialization, and polarization of the two main innate immune cell types, the macrophages and the neutrophils. The optical accessibility and the early appearance of myeloid cells that can be tracked with fluorescent labels in zebrafish embryos and the ability to use genetics to selectively ablate or expand immune cell populations have permitted studying the interaction between infection, development, and metabolism.

The inflammatory chemokine Cxcl18b exerts neutrophil-specific chemotaxis via the promiscuous chemokine receptor Cxcr2 in zebrafish.

Cxcl18b is a chemokine found in zebrafish and in other piscine and amphibian species. Cxcl18b is a reliable inflammatory marker; however, its function is yet to be elucidated. Here, we found that Cxcl18b is chemotactic towards neutrophils, similarly to Cxcl8a/Interleukin-8, the best characterised neutrophil chemoattractant in humans and teleosts.

Linking Smokers' Susceptibility to Tuberculosis with Lysosomal Storage Disorders.

Reporting in Cell, Berg et al. (2016) reveal a connection between genetic lysosomal storage disorders and the ability of macrophages to migrate and control mycobacterial infection. This insight, resulting from a zebrafish genetic screen, inspired the authors to propose an explanation for the increased susceptibility of cigarette smokers to tuberculosis.

Phagocytosis of mycobacteria by zebrafish macrophages is dependent on the scavenger receptor Marco, a key control factor of pro-inflammatory signalling.

Scavenger receptors on the cell surface of macrophages play an important role in host defence through their ability to bind microbial ligands and induce phagocytosis. Concurrently, signal transduction pathways are initiated that aid in defence mechanisms against the invading microbe. Here we report on the function of scavenger receptor Marco (Macrophage receptor with collagenous structure) during infection of zebrafish embryos with Mycobacterium marinum, a close relative of M.

The DNA damage-regulated autophagy modulator DRAM1 links mycobacterial recognition via TLR-MYD88 to autophagic defense [corrected].

Autophagy is an important defense mechanism against mycobacteria, the causative agents of tuberculosis. The molecular mechanisms that link mycobacterial recognition to autophagy remain unclear. Our analysis in zebrafish and human macrophage models of mycobacterial infection reveals that the DNA damage-regulated autophagy modulator DRAM1 functions downstream of pathogen recognition by the Toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-MYD88-NF-κB innate immune sensing pathway to activate selective autophagy.