INPP5D/SHIP1 regulates inflammasome activation in human microglia

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Microglia and neuroinflammation are key factors in Alzheimer's disease (AD) pathogenesis.
• The INPP5D/SHIP1 gene, identified through Genome-Wide Association Studies (GWAS), is linked to AD.
• Understanding INPP5D's role in microglia is crucial for AD research.

Approach:

• Confirmed INPP5D expression is primarily in adult human microglia using immunostaining and single nucleus RNA sequencing.
• Analyzed prefrontal cortex from AD patients and controls, finding reduced full-length INPP5D protein in AD brains.
• Investigated functional consequences of INPP5D reduction in human induced pluripotent stem cell-derived microglia (iMGLs) via pharmacological and genetic methods.

Key Points:

• Reduced INPP5D activity in iMGLs led to upregulated innate immune signaling and downregulated scavenger receptors.
• INPP5D inhibition triggered inflammasome activation, evidenced by increased IL-1ß and IL-18 secretion.
• Inflammasome assembly (ASC staining) and caspase-1 activation were confirmed, with inhibition reversing cytokine release.

Conclusions:

• INPP5D plays a significant role in regulating inflammasome signaling within human microglia.
• Dysregulation of INPP5D may contribute to AD pathogenesis through altered microglial inflammatory responses.
• Targeting INPP5D could offer a novel therapeutic strategy for Alzheimer's disease.