Normal And Pathologic Mechanisms Of Inflammation, Innate And Acquired Immunity

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SLPI regulation of proteolytic cascade in inflammation and cancer (40%) Enhanced inflammation, delayed healing and susceptibility to infection in the absence of SLPI suggested a link between SLPI and regulation of inflammatory responses. Following identification of annexin A2 as a SLPI-binding protein and that annexin A2 serves as a docking station for tissue-type plasminogen activator (tPA) and plasminogen to facilitate plasminogen activation and generation of plasmin, we demonstrated that the SLPI-annexin A2 interaction interrupts the proteolytic cascade responsible for plasmin generation. Moreover, we have shown that in SLPI null mice, macrophages process unregulated levels of plasmin, which contributes to excess tissue degradation, increased inflammation and failed healing following tissue injury. By inhibiting plasmin, which has a myriad of downstream consequences relative to complement activation, fibrinolysis, cytokine regulation, TGF-β activation and other inflammatory sequelae, SLPI can exert control over proteolytic and inflammatory activation networks. Because fibrinolytic processes are fundamental not only to inflammation, coagulation and tissue repair, but growing evidence highlights their dysregulation in the pathogenesis of multiple chronic inflammatory disorders, cardiovascular disease and malignancy, further defining and regulating these pathways is of major significance. Relevant to these findings, we have explored the role of SLPI as a protective agent in metastatic head and neck squamous cell carcinoma (HNSCC), which remains one of the 10 most frequently occurring cancers worldwide with a very poor prognosis, in collaboration with investigators at UMD. Our data imply that SLPI has anti-tumor activities, which may include interference with requisite proteolytic steps underlying tumor cell invasion and affecting the cell-associated plasminogen activation system, suggesting a strategy to predict (biomarker) and prevent (therapy) tumor invasive potential in oral cancer. In a model of squamous cell carcinoma in SLPI null and WT C57BL/6 mice, our evidence confirms that the absence of SLPI is associated with more rapid and extensive development of tumors, enabling characterization of the cellular and molecular pathways involved. Utilizing the 7,12-dimethylbenzαanthracene (DMBA)-induced murine skin squamous cell carcinoma (SCC) model in exploring SLPIs function in tumor development and progression, evidence supported a role for SLPI in the kinetics and incidence of skin papilloma, and in significantly inhibiting lung metastasis. However, SLPI did not appear to influence the conversion of papilloma to cancer, thereby focusing our efforts on its role in invasion, migration and metastasis. Autoimmunity and Sjogrens syndrome(SS) (30%) An important objective of our studies is to define the underlying mechanisms by which inflammatory and immune responses go awry, resulting in autoimmune pathogenesis, as exemplified by Sjogren's syndrome. The autoimmune hallmarks of SS include focal lymphoid cell infiltration of the exocrine glands (focus score) and the production of autoantibodies. The etiology of SS remains largely unknown and a conundrum is presented by the failure of many drugs that are effective in other autoimmune disorders, particularly TNFα antagonists, such as etanercept. A potential clue to the lack of efficacy of TNFα inhibitors is the elevated IL-17 in SS patients peripheral circulation, which is also unmodulated by anti-TNFα therapy. In salivary gland biopsies, we performed gene profiling to correlate specific gene expression with T cell subsets and/or their products within the inflamed tissues. At the cellular level, we have shown that expression of IL-17 and also TGF-β progressively increases with higher biopsy focus scores. Thus, we have connected IL-17 to SS tissue pathology, along with several cytokines that have been shown to be supporting molecules for development of this lineage (TGF-β, IL-23 and IL-6) without a corresponding increase in Treg with severe disease. This imbalance between pro- and anti-inflammatory forces may perpetuate the autoimmune lesions. Infectious inflammation and injury in oral mucosa (30%) Chronic periodontal diseases, which are complex, inflammatory oral diseases involving gram-negative microorganisms such as P. gingivalis (Pg), are characterized by destruction of supporting tissues surrounding the dentition. However, it has become increasingly clear that while the presence of these organisms is central to pathogenesis, the destructive process is largely host-derived. Given the seminal role of antigen presenting cells (APC) in innate and adaptive immunity, and the common lineage of monocytes, macrophages and dendritic cells, we exposed these cells to Pg and identified a Pg LPS-inducible convergent, transcriptional core response among these populations, reflected by a shared, but quantitatively distinct proteomic response. Nonetheless, despite these similarities, clear differences emerged between the myeloid populations. The finding that long-lived myeloid inflammatory cells, particularly DC, rapidly and aggressively respond to Pg LPS with generation of chemokines, proteases and cytokines capable of driving T helper cell lineage (Th17) polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation, including osteoclastogenesis. In pursuing this link, we are further examining the interaction between intact Pg bacteria (both fimbriated and non-fimbriated) and myeloid cells to delineate receptor-mediated signaling pathways linked to osteoclastogenesis and bone resorption. These studies are of additional importance since P. gingivalis, once considered to be primarily an oral pathogen, has more recently been linked to several systemic conditions, such as coronary artery disease and preterm delivery of low birth weight infants.