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Innate Immunity Mediated by TLR5 as a Novel Antiinflammatory Target for Cystic Fibrosis Lung Disease¹

Christoph J. Blohmke^*, Rachel E. Victor^*, Aaron F. Hirschfeld^*, Isaac M. Elias^*, David G. Hancock^*, Cheryl R. Lane^*, A. George F. Davidson^*, Pearce G. Wilcox, Kelly D. Smith, Joerg Overhage, Robert E. W. Hancock and Stuart E. Turvey^2,*

^* Department of Paediatrics, British Columbia Children’s Hospital and Child and Family Research Institute, iCAPTURE Centre, St. Paul’s Hospital, and Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Pathology, University of Washington, Seattle, WA 98195

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Career Development Award from the Canadian Child Health Clinician Scientist Program–a Canadian Institutes of Health Research Strategic Training Program, as well as by operating grants from the Canadian Cystic Fibrosis Foundation, the British Columbia Children’s Hospital Foundation, and the British Columbia Lung Association. C.J.B. and J.O. were supported by the Canadian Cystic Fibrosis Foundation. R.E.W.H. received funding from Genome British Columbia and was the recipient of a Canada Research Chair.

² Address correspondence and reprint requests to Dr. Stuart Turvey, British Columbia Children’s Hospital and Child and Family Research Institute, 950 West 28 Avenue, Vancouver, British Columbia V5Z 4H4, Canada. E-mail address: sturvey{at}cw.bc.ca

³ Abbreviations used in this paper: CF, cystic fibrosis; MOI, multiplicity of infection.