The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity

Abstract

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.

Keywords: COVID-19; SARS-CoV-2; cytokine; fibrinogen; fibrinolysis; inflammation; oral cavity; plasmin; salivary gland; suPAR; tPA.

Figure 1

Non-fibrinolytic and fibrinolytic functions of the plasminogen/plasmin system. Binding and subsequent plasminogen activation via plasminogen receptors (Plg-RKT, annexin 2, actin, etc.) generate plasmin. Plasmin induces proteolytic activity on the cell surface to cleave the extracellular matrix molecules necessary for cell migration. Plasmin generated by tPA on polymer fibrin, uPA, or clotting factors on activated cell surfaces dissolves fibrin and produces fibrin fragments such as D-dimers. This process is called fibrinolysis. The non-fibrinolytic functions of plasmin include proteolytic activity towards latent growth factors, the complement component C5, and pro-MMPs resulting in changes in molecule-linked signaling pathways. The cleavage of plasmin, elastase, and MMPs generate angiostatins–kringle-containing plasminogen fragments possessing anti-angiogenic properties. Abbreviations: Pm, plasmin; tPA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; ECM, extracellular matrix; MMPs, matrix metalloproteinases; suPAR, soluble urokinase plasminogen activator receptor; α2AP, α2-antiplasmin; α2MG, α2-macroglobulin.

Figure 2

Organs/tissues that contribute to the plasminogen/plasmin system in the oral cavity. Major and minor salivary glands, oral mucosae, and the periodontium play an important role in maintaining the Plg/Pm system balance in the oral cavity. Oral cavity chronic diseases and hyposalivation cause an imbalance in the Plg/Pm system in the oral cavity, supporting inflammation. Viruses, including SARS-CoV2, enter the body via the oral and nasal cavities, where the initial replication of viruses occurs. The non-fibrinolytic proteolytic function of plasmin supports the initial stages of infection with SARS-CoV-2. For example, the SARS-CoV-2 virus can enter the buccal epithelium after binding its S protein to ACE2. Plasmin cleaves the S protein of the SARS-CoV-2 virus and ENaC α, β, γ and facilitates SARS-CoV-2 infection of susceptible cells (non-fibrinolytic function). Abbreviations: tPA, tissue-type plasminogen activator; PAI-1,2, plasminogen activator inhibitor-1,2; Plg, plasminogen; uPA, urokinase-type plasminogen activator; ACE2, angiotensin-converting enzyme 2; ENaC, epithelial sodium channel.