Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Hajishengallis, George Nikos
Aging; Inflammation; Periodontology; Del-1; IL-17; LFA-1
Periodontitis--Age factors; Natural immunity; Age factors in disease
Periodontal disease arises from excessive host inflammatory responses to the tooth-associated microbial biofilm, known as dental plaque. Severity ranges from superficial inflammation of the gingivae (gingivitis) to extensive destruction of connective tissue and bone (periodontitis) leading to tooth loss. In its severe form, periodontitis affects 10 - 15% of the total human population to the extent that they will lose half their teeth by age 50. Periodontitis, a prevalent chronic disease with an impact on systemic health, such as atherosclerosis and Alzheimer's disease, is critically dependent on neutrophils. Although conventional periodontal treatment may reverse destructive inflammation, a subset of patients develops recurrent disease for reasons that are not clear, thus necessitating better understanding of the underlying immunopathology. Therefore, there is a compelling need to elucidate pathogenic mechanisms, which may be targeted for novel therapeutic intervention strategies in periodontal disease. Developmental endothelial locus-1 (Del-1) was recently identified as a novel endothelial-derived inhibitor of neutrophil extravasation. However, whether Oel-1 regulates the local tissue-specific inflammatory response and controls chronic inflammatory diseases has not been addressed yet. Upon aging, normal mice displayed increased disease accompanied by diminished Oel-1 expression. Consistent with a protective role for Oel-1 in periodontitis, Del-1-1- mice developed spontaneous inflammatory periodontal bone loss characterized by excessive local neutrophil infiltration and interleukin (IL)-17 expression. The disease was reversed in Del-1-1- mice with additional genetic deficiencies in the LFA-1 integrin or the IL-17 receptor. Strikingly, local administration of Oel-1 suppressed neutrophil infiltration and IL-17 expression in the periodontal tissue. We, therefore, concluded that Oel-1 is required for tissue homeostasis by regulating LFA-1-dependent neutrophil trafficking, inhibiting IL-17-mediated pathology, and may be a promising novel therapeutic for the treatment of inflammatory diseases. In conclusion, we showed that Oel-1, a novel inhibitor of integrindependent neutrophil adhesion, regulates local tissue-specific inflammation and controls chronic inflammatory disease. Oel-1 inhibits LFA-1-dependent neutrophil recruitment and IL-17-mediated pathology and may be a promising novel therapeutic for inflammatory diseases.
Eskan, Mehmet Akif, "Age-associated changes in innate immunity and their impacts on inflammatory disease." (2011). Electronic Theses and Dissertations. Paper 410.