ALI is caused by an uncontrolled systemic inflammatory response that results from direct (aspiration, pneumonia, ventilation-induced lung injury, etc.) or indirect injury (sepsis, hemorrhagic shock, etc.), leading to the activation of AMΦ and the sequestration of neutrophils3. Excessive recruitment of leukocytes is critical to the pathogenesis of ALI. Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemokines released by activated AMΦ36. Specifically, stimulation of AMΦ leads to the release of chemokines, which induce neutrophils to migrate from the intravascular space across the endothelium and epithelium into the airspaces27. According to the relative position of the cysteine residues, chemokines have been classified into four subfamilies (CXC, CC, C, and CX3C). Among these, MIP-2, which is also known as CXCL2, is thought to play a major role in mediating neutrophil recruitment37. Belperio J.A. et al.38 found that lung expression of MIP-2 was correlated with lung injury and neutrophil sequestration during the pathogenesis of ventilation-induced lung injury, and CXCR2−/− mice show a marked reduction in neutrophil sequestration and lung injury. Additionally, MIP-2 was shown to be up-regulated in the lungs and BALF of animals, which was associated with neutrophil accumulation in the lungs after LPS administration394041. Furthermore, Villar J. et al. showed that a CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis42. In the present study, we observed that LPS/TLR4 signaling up-regulated TLR3 expression in AMΦ. This cross talk between TLR4 and TLR3 in AMΦ resulted in the amplification of cytokine (IL-6, TNF-α) and chemokine (MIP-2, MCP-1) expression in response to LPS and Poly I:C, which activate TLR4 and TLR3, respectively, and subsequently led to enhanced PMN sequestration into the lung, which was found to be correlated with ALI based on the assessment of alveolar-capillary permeability and histological sections of lung tissue. Thus, the present study demonstrates a novel mechanism by which LPS can induce AMΦ to up-regulate TLR3 expression, through a TLR4-Myd88-NF-κB-dependent pathway, thereby sensitizing AMΦ to TLR3 ligands and promoting enhanced lung inflammation (Fig. 8).