PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen-1 signalling
| Autor: | Herter, Jan M, Margraf, Andreas, Volmering, Stephanie, Correia, Benedito Eduardo, Bradshaw, J Michael, Bisconte, Angelina, Hill, Ronald J, Langrish, Claire L, Lowell, Clifford A, Zarbock, Alexander |
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| Rok vydání: | 2018 |
| Předmět: |
Neutrophils
Knockout 1.1 Normal biological development and functioning Macrophage-1 Antigen Inbred C57BL Dose-Response Relationship Mice Underpinning research Agammaglobulinaemia Tyrosine Kinase Animals Pharmacology & Pharmacy Protein Kinase Inhibitors Mice Knockout Dose-Response Relationship Drug Liver Disease Inflammatory and immune system Pharmacology and Pharmaceutical Sciences Protein-Tyrosine Kinases Research Papers Mice Inbred C57BL Neutrophil Infiltration Drug Chemical and Drug Induced Liver Injury Digestive Diseases Signal Transduction |
| Zdroj: | British journal of pharmacology, vol 175, iss 3 |
| Popis: | Background and purposeFollowing inflammatory stimuli, neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Bruton's tyrosine kinase (Btk) is expressed in neutrophils and constitutes a promising pharmacological target for neutrophil-mediated tissue damage. Here, we evaluate a selective reversible inhibitor of Btk, PRN473, for its ability to dampen neutrophil influx via inhibition of adhesion receptor signalling pathways.Experimental approachIn vitro assays were used to assess fMLP receptor 1 (Fpr-1)-mediated binding of ligands to the adhesion receptors macrophage antigen-1 (Mac-1) and lymphocyte function antigen-1. Intravital microscopy of the murine cremaster was used to evaluate post-adhesion strengthening and endoluminal crawling. Finally, neutrophil influx was visualized in a clinically relevant model of sterile liver injury in vivo. Btk knockout animals were used as points of reference for Btk functions.Key resultsPharmacological inhibition of Btk by PRN473 reduced fMLP-induced phosphorylation of Btk and Mac-1 activation. Biochemical experiments demonstrated the specificity of the inhibitor. PRN473 (20mg·kg-1 ) significantly reduced intravascular crawling and neutrophil recruitment into inflamed tissue in a model of sterile liver injury, down to levels seen in Btk-deficient animals. A higher dose did not provide additional reduction of intravascular crawling and neutrophil recruitment.Conclusions and implicationsPRN473, a highly selective inhibitor of Btk, potently attenuates sterile liver injury by inhibiting the activation of the β2 -integrin Mac-1 and subsequently neutrophil recruitment into inflamed tissue. |
| Databáze: | OpenAIRE |
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