When Protection Turns Pathogenic: Dual Compartment Functions of Myeloid YB-1 in Renal IRI

Area of Science:

• Immunology
• Nephrology
• Molecular Biology

Background:

• Acute kidney injury (AKI) from ischemia-reperfusion injury (IRI) involves rapid innate immune activation, with myeloid cells significantly impacting injury severity.
• Y-box binding protein 1 (YB-1) has intracellular roles in inflammatory gene expression and extracellular functions, but their combined impact on early IRI is unclear.

Purpose of the Study:

• To investigate the distinct roles of intracellular myeloid YB-1 versus extracellular YB-1 in the early stages of renal IRI.
• To determine how manipulating intracellular and extracellular YB-1 affects immune responses and kidney damage during IRI.

Main Methods:

• Utilized myeloid-specific Ybx1 knockout mice (Ybx1fl/fl × LysMcre) and wild-type littermates subjected to unilateral renal IRI.
• Administered neutralizing anti-YB-1 antibody or control IgG to assess the impact of extracellular YB-1 neutralization.
• Evaluated kidney injury, inflammation, immune cell infiltration, neutrophil extracellular trap (NET) formation, and Fcγ receptor expression using molecular and histological techniques.

Main Results:

• Myeloid-specific Ybx1 knockout significantly reduced renal inflammation, neutrophil infiltration, NET formation, and tubular injury.
• Neutralizing extracellular YB-1 in knockout mice reversed protective effects, increasing inflammation, tubular damage markers (NGAL, KIM-1), neutrophil recruitment, and NET formation.
• Ybx1-deficient myeloid cells showed reduced CD16 expression, indicating impaired Fcγ receptor-mediated phagocytosis and immune complex clearance.

Conclusions:

• Myeloid YB-1 is a key regulator of early inflammatory injury in renal IRI.
• While intracellular YB-1 depletion is protective, simultaneous neutralization of extracellular YB-1 is pathogenic due to unmasked defects in immune complex clearance by myeloid cells.