Lakmali Silva
Hemostasis and Immunity Laboratory
Our laboratory aims to understand the role of the hemostatic factors (i.e., coagulation and fibrinolytic factors) in regulating inflammation at the mucosal barrier sites. The hemostatic and inflammatory systems have historically been viewed as independently functioning systems. However, it is becoming evident that these two systems are integrated biological processes that have co-evolved to fight mechanical, environmental, and pathological challenges to ultimately promote host defense against invading pathogens and maintain tissue homeostasis and proper functioning in mammalian species. The impact of such regulatory crosstalk has far-reaching implications for a wide range of diseases, including mucosal immunopathology, inflammation-driven malignancies, and autoimmune diseases. Yet, many of the mechanisms governing coagulation–inflammation crosstalk remains to be discovered.
In studying the mechanisms underlying the crosstalk between hemostasis and immunity, congenital plasminogen (Plg) deficiency in humans is a great source of evidence. These patients have either homozygous or compound heterozygous mutations in their PLG gene encoding for the active enzyme plasmin, rendering this enzyme inactive. This serine protease, plasmin, cleaves extravascular fibrin deposits that occurs because of damage caused by either physical, microbial or environmental factors. Due to lack of plasmin-mediated fibrinolysis, these patients have persistent extravascular fibrin in their mucosal barrier sites. Fibrin is a proinflammatory molecule and these patients manifest inflammatory lesions at the mucosal barrier sites, including the oral mucosa, conjunctiva, lung, genital mucosa, and the gastrointestinal tract. Interestingly, mice deficient for Plg phenocopy the human disease and thus, provide an excellent animal model to study the mechanisms underlying the inflammation mediated by the hemostatic factors.
We have demonstrated that the hemostatic factor, fibrin, mediates oral mucosal immunopathology in the absence of plasmin-mediated fibrinolysis, through activation of neutrophil effector function. We further demonstrated that this fibrin–neutrophil axis is applicable to common forms of periodontitis, an oral mucosal inflammatory disease that affects the tooth supporting structures. From these observations, it is plausible to conclude that the coagulation cascade plays a critical role in oral mucosal immunopathogenesis. However, the exact mechanism by which these factors mediate inflammation at other mucosal barrier sites is not known. Therefore, my lab focuses on investigating the mechanisms by which hemostatic factors influence the inflammatory response at the mucosal barrier sites in distinct settings, including the oral mucosa and the gastrointestinal tract.
On going projects:
1. How does fibrin as a ligand mediate neutrophil signaling and effects on downstream immune responses.
2. Role of other hemostatic factors in mediating oral mucosal immunopathology.
3. Role of hemostatic factors in mediating mucosal inflammation at other mucosal barrier sites.