Non-canonical TLR signaling restricts cytosolic LPS detection

Area of Science:

• Immunology
• Cellular Biology
• Molecular Medicine

Background:

• Intracellular lipopolysaccharide (LPS) sensing is vital for innate immunity.
• Mechanisms controlling LPS sensing for immune homeostasis remain unclear.

Purpose of the Study:

• To identify novel regulators of intracellular LPS sensing.
• To elucidate the role of MARCO in restraining inflammasome activation.

Main Methods:

• Investigated MARCO's function as an LPS sensor.
• Characterized a non-canonical Toll-like receptor (TLR) signaling pathway regulating MARCO.
• Utilized mouse models to assess the impact of MARCO deficiency on immune responses and septic shock.

Main Results:

• MARCO functions as a decoy LPS sensor, inhibiting caspase 11 and the non-canonical inflammasome.
• MARCO expression is controlled by itaconate, p62, and NRF2 via a non-canonical TLR pathway.
• IFN impairs this pathway, reducing MARCO and enhancing inflammasome activation.
• MARCO deficiency exacerbates inflammasome activation and septic shock.

Conclusions:

• MARCO is a novel LPS sensor critical for restraining non-canonical inflammasome activation.
• A non-canonical TLR pathway regulates MARCO, acting as a homeostatic switch for immune responses.
• Understanding this pathway offers insights into managing inflammation and sepsis.