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CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice.

Authors
Leichtle, A; Hernandez, M; Ebmeyer, J; Yamasaki, K; Lai, Y; Radek, K; Choung, YH; Euteneuer, S; Pak, K; Gallo, R; Wasserman, SI; Ryan, AF
Citation
Journal of immunology (Baltimore, Md. : 1950), 184(6):3087-3097, 2010
Journal Title
Journal of immunology (Baltimore, Md. : 1950)
ISSN
0022-17671550-6606
Abstract
Innate immune mechanisms are crucial in defense against bacterial illnesses in humans, as evidenced by abnormal antibacterial responses due to defects in TLR signaling, seen in children with MyD88 or IL-1R-associated kinase 4 deficiency. Otitis media (OM) is the most common disease of childhood, and the role of innate immune molecules in this disorder remains unclear. In a murine model of OM, we show that, in the absence of TNF, a key effector of innate immunity, this disease is prolonged after middle ear infection with nontypeable Haemophilus influenzae (NTHi). In the absence of TNF, mice fail to upregulate both TLRs and downstream genes and proteins, such as CCL3, resulting in defects in both inflammatory cell recruitment and macrophage function. Peritoneal macrophages of mice lacking TNF have a diminished ability to phagocytose and kill NTHi, and this defect is partially corrected in vitro by exogenous rTNF. Addition of rCCL3 alone or in combination with rTNF restores phagocytosis and killing by TNF-deficient macrophages to that of unstimulated wild-type macrophages. In vivo administration of rCCL3 to animals deficient in TNF fully restores the ability to control OM due to NTHi, whereas a CCL3-blocking Ab impaired the ability of wild-type mice to recover from OM. Thus, CCL3 is a potent downstream effector of TNF-mediated inflammation in vitro and in vivo. Manipulation of CCL3 and/or TNF may prove to be effective therapeutic approaches in OM or other conditions associated with defective TNF generation.
MeSH terms
AnimalsBlood Bactericidal Activity/genetics/*immunologyChemokine CCL3/*physiologyDisease Models, AnimalDown-Regulation/genetics/immunologyHaemophilus Infections/immunology/microbiology/prevention & controlHaemophilus influenzae/immunologyInflammation Mediators/administration & dosage/physiology/therapeutic useMacrophages, Peritoneal/*immunology/microbiology/*pathologyMiceMice, Inbred C57BLMice, KnockoutOtitis Media/genetics/immunology/pathology/*therapyPhagocytosis/genetics/*immunologyRecombinant Proteins/administration & dosage/genetics/therapeutic useToll-Like Receptors/biosynthesis/deficiencyTumor Necrosis Factor-alpha/administration & dosage/*deficiency/genetics
DOI
10.4049/jimmunol.0901167
PMID
20164426
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Otolaryngology
AJOU Authors
정, 연훈
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