Roles of TLR4 in macrophage immunity and macrophage-pulmonary vascular/lymphatic endothelial cell interactions in sepsis.

Summary

Using TLR4 knockout mice plus single-cell RNA-seq, the authors show that TLR4-deficient macrophages upregulate Abca1, increase cholesterol efflux, dampen glycolysis, and adopt M2 polarization, thereby attenuating inflammation and altering interactions with pulmonary endothelial and lymphatic endothelial cells. Endothelial TLR4 both sensitizes cells to LPS and determines susceptibility to macrophage-derived inflammatory signals. These data position TLR4 across macrophages and endothelium as a coordinated driver of sepsis-induced ALI.

Key Findings

• TLR4-deficient macrophages upregulate Abca1, enhance cholesterol efflux, reduce glycolysis, and shift toward M2 polarization.
• Macrophage metabolic and phenotypic changes modulate interactions with pulmonary ECs and LECs, attenuating inflammation.
• Endothelial TLR4 sensitizes cells to LPS and dictates susceptibility to macrophage-derived inflammatory signals, indicating multi-compartment TLR4 roles.

Clinical Implications

While preclinical, the findings suggest that therapies targeting TLR4 on both macrophages and endothelium, or modulating macrophage cholesterol efflux (e.g., ABCA1 pathways), could attenuate sepsis-induced lung injury.

Limitations

• Preclinical mouse study without human interventional validation
• Specificity of cell-type targeting strategies and potential off-target effects remain to be defined

Future Directions

Test selective, cell-targeted TLR4 inhibitors and ABCA1 modulators in sepsis models; translate signatures to human biospecimens to validate therapeutic windows.