Background: Toll-like receptors (TLRs) represent a conserved family of innate immune recognition receptors. Among TLRs, TLR4 is important for the recognition of Gram-negative bacteria, whereas TLR2 recognizes cell wall constituents of Gram-positive microorganisms, such as peptidoglycan (PGN).
Methods: To evaluate the role of TLR4 in the pathogenesis of acute lung injury induced by Escherichia coli endotoxin (lipopolysaccharide; LPS) or PGN, we compared inflammatory cell accumulation in bronchoalveolar lavage (BAL) fluid and lung pathology between C3H/HeJ (TLR4 mutant) and wild-type C3H/HeN mice. The levels of proinflammatory cytokines and chemokines in plasma and BAL fluid and nuclear factor-κB (NF-κB) translocation in the lung were also evaluated.
Results: In C3H/HeJ mice, LPS-induced neutrophil emigration was significantly decreased compared with C3H/HeN mice, whereas PGN-induced neutrophil emigration did not differ. Differential cell count in BAL fluid revealed comparable neutrophil recruitment in the alveolar space. In TLR4 mutant mice, LPS-induced upregulation of tumor necrosis factor-alpha (TNF-α), KC, and CXCL10 in plasma and BAL fluid was attenuate, which was not different after PGN. NF-κB translocation in the lung was significantly decreased in C3H/HeJ compared with C3H/HeN mice, whereas PGN-induced NF-κB translocation was not different.
Conclusion: These results suggest that TLR4 mediates inflammatory cascade induced by Gram-negative bacteria that is locally administered.
Keywords: NF-κB; TLR4; endotoxin; neutrophils; rodent.