Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier

Abstract

Fibrin gums up the works Plasmin is an abundant plasma protease that cleaves and deactivates the clot-associated protein fibrin. Human deficiencies in plasmin and its inactive proenzyme form, plasminogen (PLG), cause severe inflammation in mucosal tissues such as the mouth and eyes. Silva et al . report that, like humans, mice lacking plasminogen accumulate extravascular fibrin and develop an oral pathology that phenocopies human ligneous periodontitis (see the Perspective by Vicanolo and Hidalgo). The excess fibrin activates neutrophils through the αMβ2 (Mac-1) integrin receptor, which triggers the production of reactive oxygen species and neutrophil extracellular traps. Additionally, certain human polymorphisms in the PLG gene were found to be associated with increased likelihood of developing periodontitis, suggesting that fibrin–neutrophil interactions may be an attractive target for future treatments of this prevalent disease. —STS

PAMPs and DAMPs as the Bridge Between Periodontitis and Atherosclerosis: The Potential Therapeutic Targets

“…NETs were detected in supragingival plaque biofilms, and NETs-related protein Myeloperoxidase (MPO) was found in saliva and biofilms, which confirmed that oral bacteria isolated from plaque biofilms could stimulate the formation of NETs (Hirschfeld et al, 2015). Neutrophils in PD are recruited by fibrin through myeloid integrin α m β 2 -binding motif and activated to generate NETs (Silva et al, 2021). Studies have found that P. gingivalis (Jayaprakash et al, 2015) and Fusobacterium nucleatum (F. nucleatum) (White et al, 2014) can stimulate neutrophils to produce reactive oxygen species (ROS).…”

“…DNase I has been used as a common neutralizing agent to disrupt NETs structure to prevent DAMPs from overactivating innate immunity, and has preliminary applications in cancer treatment (Cools-Lartigue et al, 2013;White P. et al, 2016). In the periodontal destruction caused by plasminogen deficiency, the use of DNase I to remove NETs recruited and activated by excessive fibrin can significantly reduce alveolar bone resorption (Silva et al, 2021). The level of plasma DNase I of PD patients was significantly lower than healthy controls (White P. et al, 2016), indicating that the use of DNase I may contribute to the balance of nucleic acid metabolism in the circulation.…”

Airway fibrin formation cascade in allergic asthma exacerbation: implications for inflammation and remodeling

“…These findings are significant because fibrin plugs are found in casts in children with plastic bronchitis [ 41 ], and play important roles in the response acute lung injury [ 28 ]. Additionally, in support of the strong correlation between FGA, FGB and neutrophil numbers, it has been recently reported that fibrin regulates neutrophilic inflammation in oral mucosal tissues [ 42 ]. In that study, insufficient clearance of extravascular fibrin deposits engages neutrophils resulting in the production of oxidative tissue damage.…”

Neutrophils Mediate Pulmonary Artery Thrombosis In Situ

“…Neutrophil α-defensins support fibrin formation and venous thrombosis in mice [ 27 ]. Fibrin, in turn, stimulates major functions of neutrophils, such as the production of ROS and NETosis, thus forming a fibrin/neutrophil positive feedback loop that can further promote thrombosis [ 28 ]. Moreover, NETs and NLRP3 inflammasome can form a “vicious circle” supporting DVT [ 29 ].…”