A Zebrafish Drug-Repurposing Screen Reveals sGC-Dependent and sGC-Independent Pro-Inflammatory Activities of Nitric Oxide

Christine Wittmann; Markus Reischl; Asmi H Shah; Eva Kronfuss; Ralf Mikut; Urban Liebel; Clemens Grabher

doi:10.1371/journal.pone.0137286

A Zebrafish Drug-Repurposing Screen Reveals sGC-Dependent and sGC-Independent Pro-Inflammatory Activities of Nitric Oxide

PLoS One. 2015 Oct 7;10(10):e0137286. doi: 10.1371/journal.pone.0137286. eCollection 2015.

Authors

Christine Wittmann¹, Markus Reischl², Asmi H Shah¹, Eva Kronfuss¹, Ralf Mikut², Urban Liebel¹, Clemens Grabher¹

Affiliations

¹ Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
² Institute for Applied Computer Science, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.

Abstract

Tissue injury and infection trigger innate immune responses. However, dysregulation may result in chronic inflammation and is commonly treated with corticosteroids and non-steroidal anti-inflammatory drugs. Unfortunately, long-term administration of both therapeutic classes can cause unwanted side effects. To identify alternative immune-modulatory compounds we have previously established a novel screening method using zebrafish larvae. Using this method we here present results of an in vivo high-content drug-repurposing screen, identifying 63 potent anti-inflammatory drugs that are in clinical use for other indications. Our approach reveals a novel pro-inflammatory role of nitric oxide. Nitric oxide affects leukocyte recruitment upon peripheral sensory nervous system or epithelial injury in zebrafish larvae both via soluble guanylate cyclase and in a soluble guanylate cyclase -independent manner through protein S-nitrosylation. Together, we show that our screening method can help to identify novel immune-modulatory activities and provide new mechanistic insights into the regulation of inflammatory processes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Cells, Cultured
Copper Sulfate / toxicity
Drug Repositioning / methods*
Free Radical Scavengers / pharmacology
Gene Knockdown Techniques
Guanylate Cyclase / metabolism*
Inflammation / drug therapy*
Inflammation / genetics
Inflammation Mediators / pharmacology*
Larva / drug effects
Leukocytes / immunology
Morpholinos / genetics
Mucous Membrane / drug effects
Mucous Membrane / injuries
Nitric Oxide / pharmacology*
Nitric Oxide Synthase Type I / genetics
Nitric Oxide Synthase Type II / genetics
Peripheral Nervous System / drug effects
Receptors, Cytoplasmic and Nuclear / metabolism*
Soluble Guanylyl Cyclase
Zebrafish

Substances

Anti-Inflammatory Agents
Free Radical Scavengers
Inflammation Mediators
Morpholinos
Receptors, Cytoplasmic and Nuclear
Nitric Oxide
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Guanylate Cyclase
Soluble Guanylyl Cyclase
Copper Sulfate

Grants and funding

This work was supported by a Helmholtz joint project initiative between KIT and DKFZ (CW), Marie Curie International Reintegration Grant within the 7th European Community Framework Program (PIRG07-GA- 2010-267552), and the Heidelberg-Karlsruhe Research Bridge (HeiKa) (synthetic biology platform) (CG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.