Abstract
Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host’s innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4−/− and Myd88−/− mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.
Highlights
To detect the expression of TLR3 in LPS-induced AMΦ,which were isolated from the bronchoalveolar lavage fluid (BALF) of wild-type (WT) mice, LPS was administered at 5 different dosages (0, 0.01, 0.1, 1, and 10 μg/ml)
Synergy between viral and bacterial TLR signaling, which leads to amplification of the inflammatory response, has been reported previously[28]
The role of TLR4 signaling in regulating TLR3 expression was clearly shown using TLR4−/− mice
Summary
In 2001, Alexopoulou L. et al.[16] reported in Nature that following an intraperitoneal injection of LPS into mice, dramatic up-regulation of the expression of TLR3 mRNA was observed in all tissues except the thymus, suggesting that the expression of TLR3 is inducible. A high expression level of TLR mRNA was observed in lung tissue. These results raised the possibility that bacterial infection can induce sensitivity to viral infection. This observation prompted us to further investigate the mechanism of TLR4-TLR3 cross talk in AMΦ. In the present study, using both an in vivo ALI mouse model and the in vitro culture of AMΦfrom TLR4−/− and MyD88−/− mice, we demonstrate that LPS up-regulation of TLR3 in AMΦis dependent on TLR4-MyD88-NF-κB signaling.
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