Proteinase‐activated receptor‐2 up‐regulation by Fcγ‐receptor activation in human neutrophils

Abstract

We shed new light on the expression and function of the proteinase-activated receptor (PAR) family, associated with inflammation and hyperalgesia, in human granulocytes. Resting cells expressed constitutive levels of PAR-2 and PAR-3 mRNA but not PAR-1 or PAR-4. Based on flow cytometry, stimulation with opsonized bacteria (Bop) specifically up-regulated cell surface expression of PAR-2 in a concentration-dependent and time-dependent manner, independent of transcription or de novo protein synthesis. Primary granules were identified as a source of preformed PAR-2 that can readily be mobilized at the surface on fusion with the plasma membrane. Cellular response to PAR-2 activation, measured as changes in intracellular calcium concentration, was enhanced in PAR-2 up-regulated cells. Increase of cell-surface PAR-2 and of cell responsiveness were dependent specifically on the engagement of immunoglobulin (Ig)-binding receptors. Together, our results reveal that mobilization of intracellular granules, in response to Ig-receptor activation, up-regulates PAR-2 surface expression and makes neutrophils more responsive to proteinase activity. This enhanced response to PAR-2 activation indicates that molecular communication between pain and inflammation may be more important than previously believed.

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

“…However, when platelets were activated with the PAR-1 agonist, thrombin receptor-activating peptide (TRAP) (20), and then were added to neutrophils, there was robust NET formation ( Figure 1D). The addition of TRAP alone to neutrophils also induced rare NET formation ( Figure 1E), which was surprising, since human neutrophils do not express PAR-1 (21). It is known, however, that approximately 10%-20% of neutrophils circulate as neutrophil-platelet aggregates (ref.…”

Susceptibility for Lupus Nephritis by Low Copy Number of theFCGR3BGene Is Linked to Increased Levels of Pathogenic Autoantibodies

“…FCGR3B lacks a transmembrane domain and must interact with other membrane receptors such as FCGR2A and β2-integrin (CD11/CD18b) to fully activate neutrophils [30–32]. In vitro cross-linking of FCGR3B induces calcium mobilization and tyrosine phosphorylation and leads to tethering of neutrophils to immobilized ICs and IgG phagocytosis [31, 33, 34]. In healthy controls, low FCGR3B CN reduces the adherence of neutrophils to IC and subsequent IC clearance [35], and it seems reasonable to assume a similar effect in SLE patients.…”

PAR-2 expression in the gingival crevicular fluid reflects chronic periodontitis severity

“…7,8,9 A previous study by Fagundes et al, 13 also found a positive association between the greater presence of Pg-positive periodontal sites and increased PAR-2 expression. Similarly, other studies associated the presence of microorganisms with increased PAR-2 expression: Helicobacter pylori in human gastric epithelial cells, 25 Salmonella typhimurium in mouse neutrophils of peripheral blood, 26 influenza A/PR-8/34 virus in the epithelial cell airways of mice, 27 and Cryptosporidium parvum in human ileocecal epithelial cells. 28 It should be pointed out that the analyses performed in the present study did not aim to demystify the cascades of activation in which the PAR-2 is involved, or any other interaction that occurs between gingipain and the host and/or other factors involved in periodontal destruction.…”