Innate immunity mediated by TLR5 as a novel antiinflammatory target for cystic fibrosis lung disease
| Autor: | Rachel E. Victor, Isaac M. Elias, Kelly D. Smith, Christoph J. Blohmke, Pearce G. Wilcox, Robert E. W. Hancock, Cheryl R. Lane, Aaron F. Hirschfeld, David G. Hancock, Joerg Overhage, Stuart E. Turvey, A. George F. Davidson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cystic Fibrosis
medicine.medical_treatment Immunology Inflammation Biology Burkholderia cepacia medicine.disease_cause Cystic fibrosis Proinflammatory cytokine medicine Immunology and Allergy Humans Lung Innate immune system Pseudomonas aeruginosa Epithelial Cells medicine.disease Immunity Innate Toll-Like Receptor 5 Cytokine medicine.anatomical_structure TLR5 Leukocytes Mononuclear medicine.symptom Flagellin |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Novel therapies to target lung inflammation are predicted to improve the lives of people with cystic fibrosis (CF) but specific antiinflammatory targets have not been identified. The goal of this study was to establish whether TLR5 signaling is the key molecular pathway mediating lung inflammation in CF, and to determine whether strategies to inhibit TLR5 can reduce the damaging inflammatory response. The innate immune responses were analyzed in both airway epithelial cells and primary PBMCs from CF patients and matched controls. Additionally, 151 clinical isolates of Pseudomonas aeruginosa from CF patients were assessed for motility and capacity to activate TLR5. Blood and airway cells from CF patients produced significantly more proinflammatory cytokine than did control cells following exposure to the CF pathogens P. aeruginosa and Burkholderia cepacia complex (p < 0.001). Stimulation with pure TLR ligands demonstrated that TLR signaling appears to mediate the excessive cytokine production occurring in CF. Using complementary approaches involving both neutralizing Ab targeting TLR5 and flagellin-deficient bacteria, we established that inhibition of TLR5 abolished the damaging inflammatory response generated by CF airway cells following exposure to P. aeruginosa (p < 0.01). The potential therapeutic value of TLR5 inhibition was further supported by our demonstration that 75% of clinical isolates of P. aeruginosa retained TLR5 activating capacity during chronic CF lung infection. These studies identify the innate immune receptor TLR5 as a novel antiinflammatory target for reducing damaging lung inflammation in CF. |
| Databáze: | OpenAIRE |
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