TNFSF15 Promotes Antimicrobial Pathways in Human Macrophages and These Are Modulated by TNFSF15 Disease-Risk Variants

Area of Science:

• Immunology
• Genetics
• Microbiology

Background:

• Genetic variants in TNFSF15 are associated with inflammatory bowel disease (IBD) risk.
• TNFSF15 influences inflammatory responses, with potential roles beyond T cells, including in macrophages.

Purpose of the Study:

• To investigate the role of TNFSF15 in antimicrobial pathways within human macrophages.
• To determine if TNFSF15-mediated pathways in macrophages offer an advantage in IBD risk carriers.

Main Methods:

• Human monocyte-derived macrophages were analyzed for protein expression, signaling, bacterial uptake, and clearance.
• Techniques included flow cytometry, ELISA, and gentamicin protection assays.

Main Results:

• TNFSF15, via DR3, is essential for pattern-recognition-receptor (PRR)-induced bacterial clearance.
• TNFSF15 upregulates bacterial uptake and intracellular clearance through ROS, NOS2, and autophagy.
• Macrophages from IBD risk carriers with high TNFSF15 expression exhibited enhanced antimicrobial pathway activity.

Conclusions:

• Autocrine/paracrine TNFSF15 is crucial for optimal PRR-enhanced antimicrobial pathways in macrophages.
• Mechanisms of TNFSF15-dependent bacterial clearance were defined.
• The study determined how TNFSF15 IBD risk genotypes modulate these antimicrobial outcomes.