Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone Suppresses the Secretory Processes That Ensure the Invasion of Neutrophils into Tissues and Induce Inflammation

Abstract

Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients with cystic fibrosis or viral diseases. Hyaluronic acid (HA) plays an important role in the recruitment of neutrophils to tissues. 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, is used to treat inflammation, but its mechanism of action is unknown. We studied the effect of 4-MU on neutrophil adhesion and concomitant secretion using adhesion to fibronectin as a model for integrin-dependent adhesion. 4-MU reduced the spreading of neutrophils on the substrate and the concomitant secretion of granule proteins, including pro-inflammatory components. 4-MU also selectively blocked adhesion-induced release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, which can influence cell invasion by modifying the extracellular matrix. Finally, 4-MU inhibited the formation of cytonemes, the extracellular membrane secretory structures containing the pro-inflammatory bactericides of the primary granules. The anti-inflammatory effect of 4-MU may be associated with the suppression of secretory processes that ensure the neutrophil invasion and initiate inflammation. We suggest that HA, due to the peculiarities of its synthesis, can promote the release of secretory carriers from the cell and 4-MU can block this process.

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

“…An increase in hydroxylysine release may be inhibited by minoxidil, a lysyl hydroxylase inhibitor, indicating lysyl hydroxylase activation upon adhesion [ 16 ]. A statistically significant increase in hydroxylysine release was observed when neutrophils attached to fibronectin in the presence of insulin or LPS [ 15 , 49 ]. In both cases, the stimulation of hydroxylysine release was selective, since both drugs had little effect on the secretion of other amino acids.…”

Early detection of hepatobiliary involvement in cystic fibrosis: Biomarkers, radiologic methods, and genetic influences

“…23,50,51 However, these tests are expensive and not widely available in clinical settings. The results of these direct biomarkers can also be confounded by other fibrotic processes seen in CF, [61][62][63] and have not resulted in improved diagnostic accuracy compared to the conventional markers outlined above. 64,65…”

Neutrophils, Fast and Strong

“…Mechanisms of adhesion and secretion in neutrophils play an important role in neutrophilic inflammation, and hyaluronic acid (HA) mediates the recruitment of neutrophils into tissues [ 15 ]. The study of the 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, on the secretory processes in neutrophils revealed anti-inflammatory effects of 4-MU; 4-MU reduced secretion of granule proteins, including pro-inflammatory components [ 16 ], which may be the basis for therapeutic use of 4-MU.…”