title: CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice.
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.
authors.affiliation: Division of Otolaryngology, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Anke
authors.initials: A
authors.lastname: Leichtle
authors.forename: Michelle
authors.initials: M
authors.lastname: Hernandez
authors.forename: Joerg
authors.initials: J
authors.lastname: Ebmeyer
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Yuping
authors.initials: Y
authors.lastname: Lai
authors.forename: Katherine
authors.initials: K
authors.lastname: Radek
authors.forename: Yun-Hoon
authors.initials: YH
authors.lastname: Choung
authors.forename: Sara
authors.initials: S
authors.lastname: Euteneuer
authors.forename: Kwang
authors.initials: K
authors.lastname: Pak
authors.forename: Richard
authors.initials: R
authors.lastname: Gallo
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Wasserman
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
mesh_terms: D000818:Animals; D001770:Blood Bactericidal Activity / Q000235:genetics / Q000276:immunology*; D054405:Chemokine CCL3 / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D006193:Haemophilus influenzae / Q000276:immunology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010033:Otitis Media / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D051193:Toll-Like Receptors / Q000096:biosynthesis / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D018836:Inflammation Mediators; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha