title: Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia.
abstract: Toll like receptors play an important role in lung host defense against bacterial pathogens. In this study, we investigated independent and cooperative functions of TLR4 and TLR9 in microbial clearance and systemic dissemination during Gram-negative bacterial pneumonia. To access these responses, wildtype Balb/c mice, mice with defective TLR4 signaling (TLR4(lps-d)), mice deficient in TLR9 (TLR9(-/-)) and TLR4/9 double mutant mice (TLR4(lps-d)/TLR9(-/-)) were challenged with K. pneumoniae, then time-dependent lung bacterial clearance and systemic dissemination determined. We found impaired lung bacterial clearance in TLR4 and TLR9 single mutant mice, whereas the greatest impairment in clearance was observed in TLR4(lps-d)/TLR9(-/-) double mutant mice. Early lung expression of TNF-alpha, IL-12, and chemokines was TLR4 dependent, while IFN-gamma production and the later expression of TNF-alpha and IL-12 was dependent on TLR9. Classical activation of lung macrophages and maximal induction of IL-23 and IL-17 required both TLR4 and TLR9. Finally, the i.t. instillation of IL-17 partially restored anti-bacterial immunity in TLR4(lps-d)/TLR9(-/-) double mutant mice. In conclusion, our studies indicate that TLR4 and TLR9 have both non-redundant and cooperative roles in lung innate responses during Gram-negative bacterial pneumonia and are both critical for IL-17 driven antibacterial host response.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America. ubhan@med.umich.edu
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhan
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.forename: Xianying
authors.initials: X
authors.lastname: Zeng
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Newstead
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cornicelli
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006090:Gram-Negative Bacteria / Q000235:genetics*; D018664:Interleukin-12 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics*; D007711:Klebsiella pneumoniae / Q000235:genetics; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018410:Pneumonia, Bacterial / Q000378:metabolism* / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12