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

Abstract

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we document that the clotting factor fibrin is a critical regulator of neutrophil function at mucosal barriers. We demonstrate that fibrin engages neutrophils through the αMβ2 integrin receptor and activates effector functions, including the production of reactive oxygen species and NET formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis. Indeed, the accumulation of fibrin due to Mendelian genetic defects in plasmin leads to severe oral mucosal immunopathology in mice and humans. Concordantly, genetic polymorphisms in the human PLG gene, encoding plasminogen, are associated with common forms of the oral mucosal disease periodontitis. Our work uncovers fibrin as a critical regulator of neutrophil effector function within the mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in common mucosal disease.

Persistent Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19

“…In fact, excessive release of NETs, with low resolution of inflammation, can lead to immune thrombosis within blood vessels, and the NET-fibrin interactions can contribute to the severity of tissue injury and pathogenesis 56 . Unique to the oral organ, the NETs-fibrin axis plays a unique role to regulate constant deposition of fibrin produced by the commensal-triggered inflammation 57 . Our proteomic analyses also revealed significant correlations between salivary fibrinogen and salivary annexin-1.…”

“…Indeed, excessive release of NETs, with a low resolution of inflammation, can lead to immune thrombosis in blood vessels, with NET-fibrin interactions contributing to the severity of tissue injury and pathogenesis ( 45 ). Unique to the oral organ, the NET-fibrin axis also plays a unique role in regulating the constant deposition of fibrin produced by the commensal microbiome-triggered inflammation ( 46 ).…”

Neutrophils Orchestrate the Periodontal Pocket

“…The genetic backdrop of all forms of early-onset periodontitis is based on inborn neutrophil defects ( 18 , 63 ) or on other inborn genetic defects leading to neutrophil activation ( 64 ). The concomitant dysbiosis in early-onset periodontitis is hence a consequence of inborn immune deficiency.…”

“…In contrast, aggNETs proteolytically inactivate several soluble pro-inflammatory mediators over time ( 140 ). Neutrophil activation due to plasminogen (Plg) deficiency causes periodontitis in both humans (known as ligneous periodontitis) ( 141 ) and Plg -/- mice ( 64 ). The neutrophil activation in Plg deficiency is effected via fibrin polymer binding motif recognisable by the integrin αmβ2 (CD11b/CD18) ( 142 ) and results in exaggerated NET formation in Plg -/- mice.…”

“…The neutrophil activation in Plg deficiency is effected via fibrin polymer binding motif recognisable by the integrin αmβ2 (CD11b/CD18) ( 142 ) and results in exaggerated NET formation in Plg -/- mice. The exaggerated NET formation effectuates heavy periodontitis, which can be suppressed by DNase I in a mouse model ( 64 ). Exaggerated NET formation is concomitant with heavy purulent periodontitis ( 6 ).…”