TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury

Xibing Ding, Shuqing Jin, Yao Tong, Xi Jiang, Zhixia Chen, Shuya Mei, Liming Zhang, Timothy R. Billiar, Quan Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AM) 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 AM from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4 and Myd88 mice and following pretreatment with a NF-B inhibitor. The enhanced TLR3 up-regulation in AM 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 AM-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-B 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.

Original languageEnglish
Article number34278
JournalScientific Reports
StatePublished - 15 Feb 2017
Externally publishedYes


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