Monocytic thrombomodulin triggers LPS- and gram-negative bacteria-induced inflammatory response

Area of Science:

• Immunology
• Cell Biology
• Pathophysiology

Background:

• Sepsis, a life-threatening condition, arises from the body's overreaction to bacterial infection.
• The precise role of monocytic membrane-bound thrombomodulin (TM) in lipopolysaccharide (LPS)-induced inflammation was previously unclear.

Purpose of the Study:

• To elucidate the function of monocytic TM in LPS-induced inflammatory signaling and sepsis.
• To investigate the interaction of monocytic TM with LPS receptors and its role in gram-negative bacterial infections.

Main Methods:

• Utilized human monocytic cells with TM knockdown to assess inflammatory pathways and cytokine production.
• Employed coimmunoprecipitation and immunofluorescence assays to determine TM's interaction with CD14 and TLR4/myeloid differentiation factor-2 (MD-2).
• Established myeloid-specific TM-deficient mice to evaluate in vivo sepsis outcomes following Klebsiella pneumoniae infection and cecal ligation and puncture.

Main Results:

• TM knockdown in monocytic cells significantly attenuated LPS-induced signaling and cytokine release.
• Monocytic TM was found to interact with the CD14/TLR4/MD-2 complex, indicating its involvement in LPS recognition.
• TM deficiency in myeloid cells of mice led to improved survival, reduced systemic inflammation, and enhanced resistance to bacterial dissemination during sepsis models.
• Increased neutrophil infiltration was observed in TM-deficient mice, potentially contributing to reduced bacterial spread.

Conclusions:

• Monocytic TM is a novel component of the CD14/TLR4/MD-2 complex, actively participating in LPS- and gram-negative bacteria-induced inflammatory responses.
• Targeting monocytic TM may offer a therapeutic strategy for mitigating sepsis severity and improving patient outcomes.