title: Mucosal sensitization to German cockroach involves protease-activated receptor-2.
abstract: BACKGROUND
  Allergic asthma is on the rise in developed countries. A common characteristic of allergens is that they contain intrinsic protease activity, and many have been shown to activate protease-activated receptor (PAR)-2 in vitro. The role for PAR-2 in mediating allergic airway inflammation has not been assessed using a real world allergen.
  
  
  METHODS
  Mice (wild type or PAR-2-deficient) were sensitized to German cockroach (GC) feces (frass) or protease-depleted GC frass by either mucosal exposure or intraperitoneal injection and measurements of airway inflammation (IL-5, IL-13, IL-17A, and IFNgamma levels in the lung, serum IgE levels, cellular infiltration, mucin production) and airway hyperresponsiveness were performed.
  
  
  RESULTS
  Following systemic sensitization, GC frass increased airway hyperresponsiveness, Th2 cytokine release, serum IgE levels, cellular infiltration and mucin production in wild type mice. Interestingly, PAR-2-deficient mice had similar responses as wild type mice. Since these data were in direct contrast to our finding that mucosal sensitization with GC frass proteases regulated airway hyperresponsiveness and mucin production in BALB/c mice (Page et. al. 2007 Resp Res 8:91), we backcrossed the PAR-2-deficient mice into the BALB/c strain. Sensitization to GC frass could now occur via the more physiologically relevant method of intratracheal inhalation. PAR-2-deficient mice had significantly reduced airway hyperresponsiveness, Th2 and Th17 cytokine release, serum IgE levels, and cellular infiltration compared to wild type mice when sensitization to GC frass occurred through the mucosa. To confirm the importance of mucosal exposure, mice were systemically sensitized to GC frass or protease-depleted GC frass via intraperitoneal injection. We found that removal of proteases from GC frass had no effect on airway inflammation when administered systemically.
  
  
  CONCLUSIONS
  We showed for the first time that allergen-derived proteases in GC frass elicit allergic airway inflammation via PAR-2, but only when allergen was administered through the mucosa. Importantly, our data suggest the importance of resident airway cells in the initiation of allergic airway disease, and could make allergen-derived proteases attractive therapeutic targets.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA. kristen.page@cchmc.org
authors.forename: Kristen
authors.initials: K
authors.lastname: Page
authors.forename: John R
authors.initials: JR
authors.lastname: Ledford
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Krista
authors.initials: K
authors.lastname: Dienger
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D003058:Cockroaches / Q000201:enzymology / Q000276:immunology*; D005243:Feces / Q000201:enzymology; D018928:Immunity, Mucosal; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D019476:Insect Proteins / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000008:administration & dosage / Q000276:immunology*; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D000485:Allergens; D019476:Insect Proteins; D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D009077:Mucins; D044464:Receptor, PAR-2; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010447:Peptide Hydrolases