Browsing School, Graduate by Subject "IL-17"
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Th17 Cells in Gingival Immunity and Their Key Role in Periodontitis PathogenesisPeriodontitis is a very common human disease characterized by inflammatory bone destruction in the oral cavity. It affects more than 64 million adults in the United States and is often linked to systemic or distant co-morbidities. T helper (Th) cells and specifically Th17 have been identified as important constituents of the inflammatory lesion in periodontitis. However, the specific role of Th17 cells in periodontitis and whether they drive inflammatory pathology is not fully understood. We performed a detailed characterization of gingival tissues and found that Th17 are amplified in the lesions of human periodontitis. In fact, Th17 cells represent the major source of IL-17A in humans and in animal models of periodontitis and we show that their accumulation in gingival tissues is IL-6 dependent. Th17 differentiation and IL-17A expression are tightly regulated by signal transducer and activator of transcription-3 (STAT3). To analyze the role of Th17/STAT3 in humans with periodontitis we have evaluated a large cohort of patients with autosomal dominant mutations in STAT3. Autosomal Dominant Hyper IgE Syndrome (AD-HIES) patients have a defect in Th17 differentiation and lack Th17 cells in the circulation. We clinically characterized patients with AD-HIES and evaluated Th17 responses in their oral tissues. We find that AD-HIES patients have reduced susceptibility to periodontitis and present minimal oral inflammation, consistent with blunted Th17 tissue responses. To mechanistically dissect the role of Th17 cells and STAT3 in periodontitis, we performed periodontitis induction in mouse models specifically lacking Th17 cells. Cd4creStat3floxed mice lacked Th17 cells but other sources of IL-17 producing cells were unaffected in gingival tissues and importantly, were resistant to inflammatory bone loss. These results demonstrate the key role of Th17 in periodontitis and suggest inhibition of Th17 through Stat3 in the treatment/prevention of disease. Indeed, we performed preclinical studies of Stat3 inhibition (using C188-9 inhibitor, a small-molecule compound designed to prevent Stat3 activation) and demonstrated that pharmacologic inhibition of Stat3 prevented inflammatory bone loss in periodontitis models. Our work uncovers the pathogenic potential of Th17 cells in periodontal inflammatory bone loss and suggests pharmacologic inhibition through STAT3 in the prevention of this common inflammatory disease.
Th17-associated immune responses are required for resolution of Staphylococcus aureus nasal carriageThe anterior nares of humans are the major reservoir for Staphylococcus aureus colonization. Approximately 20% of the healthy human population is persistently and 80% intermittently colonized with S. aureus in the nasal cavity. Previous studies have shown a strong causal connection between S. aureus carriage and increased risk of nosocomial infection, as well as increased carriage due to immune dysfunction. However, the immune responses that permit persistence or mediate clearance are undefined. We developed a carriage model in C57BL/6J mice and showed that clearance begins 14 days post-inoculation. In contrast, SCID mice that have a deficient adaptive immune response are unable to eliminate S. aureus even after 28 days post-inoculation. Furthermore, decolonization was found to be T-cell mediated, but B-cell independent by evaluating carriage clearance in TCR-beta/delta KO and IgH-mu KO mice, respectively. Up-regulation of IL-1beta, KC, IL-17A and IL-17F occurred following inoculation with intra-nasal S. aureus. IL-17A production was crucial for clearance since IL-17A-deficient mice were unable to eliminate S. aureus carriage. In addition, inoculation of IL-17A/F KO mice displayed a significant inability to control S. aureus growth in the nares. Subsequently, cell differential counts were evaluated from nasal lavage fluid obtained from wild type and IL-17A-deficient colonized mice. These counts displayed IL-17A-dependent neutrophil migration. Antibody-mediated depletion of neutrophils in colonized mice caused reduced clearance compared to isotype treated controls. Th17-associated responses are reported to induce antimicrobial peptide production at epithelial surfaces. Therefore, we utilized RT-PCR to determine nasal tissue expression following inoculation with S. aureus of three antimicrobial peptides with anti-staphylococcal activity, mouse CRAMP, beta-defensin-3 (mBD-3), and beta-defensin-14 (mBD-14). We elucidated an IL-17A-dependent up-regulation of antimicrobial peptides post-S. aureus inoculation, and enhanced nasal tissue expression of mouse beta-defensin-3 upon IL-17A stimulation. Additionally, we discovered that ex-vivo nasal tissue supernatants have anti-staphylococcal activity that is solute-dependent and heat-sensitive. Our data suggest that the Th17-associated immune response is required for nasal decolonization. This response is T-cell dependent, mediated via IL-17F and IL-17A production, neutrophil influx, and potentially antimicrobial peptide induction. Th17-associated immune responses may be targeted for strategies to mitigate distal infections originating from persistent S. aureus carriage in humans.