Neutrophilia, gelatinase release and microvascular leakage induced by human mast cell tryptase in a mouse model: Lack of a role of protease‐activated receptor 2 (PAR2)

Abstract

SummaryBackgroundTryptase, the most abundant protease of the human mast cell, has been implicated as a key mediator of allergic inflammation that acts through activation of PAR2.ObjectivesTo investigate the contribution of PAR2 in the pro‐inflammatory actions mediated by tryptase in a mice model.MethodsWe have injected recombinant human βII‐tryptase into the peritoneum of PAR2‐deficient and wild‐type C57BL/6 mice. After 6, 12 and 24 hours, mice were killed, peritoneal lavage performed and inflammatory changes investigated.ResultsTryptase stimulated an increase in neutrophil numbers in the peritoneum, but responses did not differ between PAR2‐deficient and wild‐type mice. Heat inactivation of tryptase or pre‐incubation with a selective tryptase inhibitor reduced neutrophilia, but neutrophil accumulation was not elicited with a peptide agonist of PAR2 (SLIGRL‐NH 2). Zymography indicated that tryptase stimulated the release of matrix metalloproteinases (MMP) 2 and 9 in the peritoneum of both mouse strains. Studies involving immunomagnetic isolation of neutrophils suggested that neutrophils represent the major cellular source of tryptase‐induced MMP2 and MMP9. At 24 hours after tryptase injection, there was increased microvascular leakage as indicated by high levels of albumin in peritoneal lavage fluid, and this appeared to be partially abolished by heat‐inactivating tryptase or addition of a protease inhibitor. There was no corresponding increase in levels of histamine or total protein. The extent of tryptase‐induced microvascular leakage or gelatinase release into the peritoneum did not differ between PAR2‐deficient and wild‐type mice.ConclusionsOur findings indicate that tryptase is a potent stimulus for neutrophil accumulation, MMP release and microvascular leakage. Although these actions required an intact catalytic site, the primary mechanism of tryptase in vivo would appear to involve processes independent of PAR2.

Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation

“…PARs activate ERK1/2, JNK, and p38 MAPKs to induce cellular responses in the brain cells that also induces the secretion of inflammatory cytokines and chemokines [67]. Previous study has shown that mast cell proteases upregulate neuroinflammation via activating glial cells and neurons to release TNF-α and IL-6 through PAR-2 expression [71]. PAR-2 expressed on glia, neurons and mast cells upregulate neuroinflammation in the CNS [72–75].…”

Expression of Inflammatory Markers RANK, MMP-9 and PTHrP in Chronic Apical Periodontitis from People Living with HIV Undergoing Antiretroviral Therapy

“…After birth, its expression is present in large cells on bone surfaces, presumably osteoclasts [ 34 ]. Recently, MMP-9 expression was related to the number of neutrophils present in the inflammatory zones [ 35 ]. MMPs, in general, are involved in apical periodontitis through their relationship with the clinical characteristics of the disease, in the severity of bone destruction, and tend to have an increased expression in lesions greater than 7 mm, especially MMP-1, 2 and 9.…”

Pruritogens in pemphigoid diseases: Possible therapeutic targets for a burdensome symptom

“…37,38 However, others reported that the number of infiltrated mast cells in BP lesional skin is not increased compared to healthy controls and does not correlate with pruritus severity. 39 Taken together, mast cellderived histamine likely does not play a significant role in BPassociated pruritus or may contribute exclusively to the pruritus Dupilumab (BP) [68][69][70] Tralokinumab, lebrikizumab 72 IL-31 Activation of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) on cutaneous sensory neurons [77][78][79][80][81][82][83] • Inconsistent serum levels in BP 74,84,85 Tryptase Activation of PAR-2 receptor and direct stimulation of cutaneous sensory neurons [110][111][112][113] • Elevated levels in BP blister fluid and sera [118][119][120] • Tryptase-positive mast cells in BP b39 • Increased tryptase-positive cells in LAD 122 -Nafamostat…”