Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Macrophage podoplanin (PDPN) expression is crucial in sepsis, but its regulation by Toll-like receptor 4 (TLR4) and impact on macrophage function are unclear.
• Understanding PDPN regulation is key to developing novel sepsis therapies.

Purpose of the Study:

• To elucidate the regulatory mechanism of TLR4-stimulated PDPN upregulation in macrophages.
• To investigate the role of PDPN expression in macrophage function and sepsis outcome.

Main Methods:

• Utilized in vitro and in vivo models of sepsis, including ADAP-deficient and wild-type (WT) mice.
• Employed macrophage stimulation assays, genetic manipulation (ADAP deficiency), and pharmacological interventions.
• Investigated signaling pathways including Bruton's tyrosine kinase (BTK), mTOR, and STAT3.

Main Results:

• PDPN upregulation in TLR4-stimulated macrophages requires adhesion and degranulation-promoting adapter protein (ADAP).
• ADAP deficiency leads to reduced PDPN expression and exacerbates sepsis severity.
• A distinct PDPN-high (PDPNhi) peritoneal macrophage subset with M2-like phenotype and enhanced phagocytic activity is generated in WT but not ADAP-deficient mice.
• BTK-mediated ADAP phosphorylation, in conjunction with mTOR, activates STAT3, leading to PDPN promoter transactivation.
• STAT3 activation potentiates PDPNhi macrophage generation and alleviates sepsis severity.

Conclusions:

• ADAP is a critical regulator of TLR4-induced PDPN expression in macrophages during sepsis.
• ADAP-mediated PDPN upregulation resets macrophage function, enhancing innate immune defense against sepsis.
• Targeting the ADAP-STAT3 pathway offers a potential therapeutic strategy for sepsis.