Luteolin Ameliorates Sepsis-Induced Acute Lung Injury by Targeting RPTPα to Reprogram Macrophage M1-M2 Polarization

Area of Science:

• Immunology
• Pharmacology
• Biochemistry

Background:

• Sepsis-induced acute lung injury (ALI) involves dysregulated macrophage polarization.
• Novel therapeutic targets are needed for effective ALI treatment.
• Precision medicine approaches are crucial for advancing ALI therapies.

Purpose of the Study:

• To investigate luteolin's (LU) effect on macrophage polarization in sepsis-induced ALI.
• To identify the cellular target of LU in macrophages.
• To explore LU as a potential therapeutic agent for ALI.

Main Methods:

• Luteolin (LU) treatment on macrophages and inflammation models.
• Thermal proteome profiling, drug affinity responsive target stability, microscale thermophoresis, and surface plasmon resonance assays to identify LU's target.
• Molecular docking to predict LU-target interaction.
• Transcriptomic profiling, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to analyze molecular pathways.
• In vivo studies using mouse and zebrafish models.

Main Results:

• Luteolin (LU) promotes M1-to-M2 macrophage polarization and modulates cytokine expression.
• Receptor-type protein tyrosine phosphatase alpha (RPTPα) identified as a direct cellular target of LU.
• LU inhibits RPTPα phosphatase activity by interacting with the ⁴⁰⁵PFTP⁴⁰⁸ motif.
• LU suppresses tumor necrosis factor (TNF) signaling pathways, an effect reversed by RPTPα silencing.
• LU demonstrates potent anti-inflammatory effects in vivo models of ALI and inflammation.

Conclusions:

• Receptor-type protein tyrosine phosphatase alpha (RPTPα) is a potential therapeutic target for modulating macrophage polarization in sepsis-induced ALI.
• Luteolin (LU) shows promise as a lead compound targeting RPTPα for the treatment of sepsis-induced ALI.