Platelet factor 4 (CXCL4/PF4) upregulates matrix metalloproteinase-2 (MMP-2) in gingival fibroblasts

Abstract

Periodontitis is a chronic inflammatory disease characterized by the release of matrix metalloproteinases (MMPs) from resident connective tissue cells in tooth-supporting tissues (periodontium). Platelet activation, and the attendant release of pro-inflammatory chemokines such as platelet factor 4 (CXCL4/PF4), are associated with periodontitis although the associated biochemical pathways remain undefined. Here we report that recombinant PF4 is internalized by cultured human gingival fibroblasts (hGFs), resulting in significant (p < 0.05) upregulation in both the production and release of MMP-2 (gelatinase A). This finding was corroborated by elevated circulating levels of MMP-2 (p < 0.05) in PF4-overexpressing transgenic mice, relative to controls. We also determined that PF4 induces the phosphorylation of NF-κB; notably, the suppression of NF-κB signaling by the inhibitor BAY 11-7082 abrogated PF4-induced MMP-2 upregulation. Moreover, the inhibition of surface glycosaminoglycans (GAGs) blocked both PF4 binding and NF-κB phosphorylation. Partial blockade of PF4 binding to the cells was achieved by treatment with either chondroitinase ABC or heparinase III, suggesting that both chondroitin sulfate and heparan sulfate mediate PF4 signaling. These results identify a novel pathway in which PF4 upregulates MMP-2 release from fibroblasts in an NF-κB- and GAG-dependent manner, and further our comprehension of the role of platelet signaling in periodontal tissue homeostasis.

Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors

“…Using the double knockout strain, we wanted to make sure that only effects related to the C5aR1-CXCL4 axis were investigated, because CXCL4-deficient mice display a number of phenotypes related to platelets and thrombosis, 72 as well as immune functions, 73 , 74 and further functions 75 such as tissue remodeling. 76 , 77 When characterizing these mice, we observed distinct effects of these molecules. Regarding platelet activation as assessed by platelet activation markers (fibrinogen binding or adhesion capacity), the absence of C5aR1 and CXCL4 resulted in reduced platelet reactivity.…”

Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review

“…Upon activation, granules containing proteins with hemostatic functions are transferred to platelet membrane and released to extracellular space to further promote platelet adhesion and activation [ 102 ]. The lung autopsies of COVID-19 patients showed upregulated platelet expression of PF4 (CXCL4), which promotes blood coagulation and activates the NF-κB signaling pathway in ECs, acting as a potential agent of both thrombosis and inflammation [ 4 , 103 ]. Anti-PF4 antibodies may be involved in the pathophysiology of severe clinical complications of COVID-19 [ 104 ].…”

“…Cytokines, especially IL-1 and IL-6, and chemokines are involved in all phases of inflammation and thrombosis, using multiple biological pathways [ 18 , 29 , 43 , 44 , 45 , 50 , 51 , 58 , 59 , 60 , 61 , 62 , 66 , 69 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 93 , 94 , 101 , 103 , 129 , 132 , 136 , 137 , 138 ].…”

“…Thrombocytopathy, abnormal hyper-reactivity phenotypes, and significantly elevated levels of platelet adhesion and activation mediators contribute to immunothrombi, especially in severe and critical SARS-CoV-2 infection [ 2 , 4 , 11 , 16 , 19 , 94 , 95 , 96 , 97 , 100 , 101 , 102 , 103 , 104 , 105 , 113 , 114 , 115 , 127 ].…”