Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice.
We previously found CC chemokine ligand 3 (CCL3) to be a potent effector of inflammation during otitis media (OM): exogenous CCL3 rescues the OM phenotype of tumor necrosis factor-deficient mice and the function of macrophages deficient in several innate immune molecules. To further delineate the role of CCL3 in OM, we evaluated middle ear (ME) responses of ccl3-/-mice to nontypeable Haemophilus influenzae (NTHi). CCL chemokine gene expression was evaluated in wild-type (WT) mice during the complete course of acute OM. OM was induced in ccl3-/- and WT mice, and infection and inflammation were monitored for 21 days. Phagocytosis and killing of NTHi by macrophages were evaluated by an in vitro assay. The nasopharyngeal bacterial load was assessed in naive animals of both strains. Many CCL genes showed increased expression levels during acute OM, with CCL3 being the most upregulated, at levels 600-fold higher than the baseline. ccl3-/- deletion compromised ME bacterial clearance and prolonged mucosal hyperplasia. ME recruitment of leukocytes was delayed but persisted far longer than in WT mice. These events were linked to a decrease in the macrophage capacity for NTHi phagocytosis and increased nasopharyngeal bacterial loads in ccl3-/- mice. The generalized impairment in inflammatory cell recruitment was associated with compensatory changes in the expression profiles of CCL2, CCL7, and CCL12. CCL3 plays a significant role in the clearance of infection and resolution of inflammation and contributes to mucosal host defense of the nasopharyngeal niche, a reservoir for ME and upper respiratory infections. Therapies based on CCL3 could prove useful in treating or preventing persistent disease.
['Deniffel|Dominik|D|', 'Nuyen|Brian|B|', 'Pak|Kwang|K|', 'Suzukawa|Keigo|K|', 'Hung|Jun|J|', 'Kurabi|Arwa|A|', 'Wasserman|Stephen I|SI|', 'Ryan|Allen F|AF|']
D000818:Animals D058491:Bacterial Load D002465:Cell Movement D018932:Chemokine CCL2 D054405:Chemokine CCL3 D054410:Chemokine CCL7 D004195:Disease Models, Animal D004432:Ear, Middle D005786:Gene Expression Regulation D006192:Haemophilus Infections D006193:Haemophilus influenzae D054884:Host-Pathogen Interactions D007962:Leukocytes D008264:Macrophages D051379:Mice D018345:Mice, Knockout D018945:Monocyte Chemoattractant Proteins D009305:Nasopharynx D010033:Otitis Media D010587:Phagocytosis D015398:Signal Transduction
otitis media chemokines innate immunity nontypeable Haemophilus influenzae mucosal flora nasopharyngeal culture