The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C

Area of Science:

• Neurobiology
• Immunology
• Cell Biology

Background:

• Lysosome dysfunction is common in neurodegenerative diseases and lysosomal storage diseases.
• Microglia are vulnerable to lysosome dysfunction due to phagocytic stress.
• CD22 regulates microglial homeostasis in mice, and soluble CD22 (sCD22) is elevated in Niemann-Pick type C disease (NPC) patients.

Purpose of the Study:

• To investigate the role of CD22 in the human brain, particularly in microglia.
• To identify the binding partner of sCD22 on human myeloid cells.
• To explore the therapeutic potential of targeting the sCD22-ligand interaction for NPC treatment.

Main Methods:

• Expression analysis of CD22 in the human brain.
• Identification of sCD22 binding partners using genetic and proteomic screens.
• Functional assays using induced pluripotent stem cell (iPSC)-derived microglia-like cells from NPC patients.
• In vitro testing of CD22 blocking antibodies.

Main Results:

• CD22 is expressed by oligodendrocytes in the human brain, unlike in mice.
• sCD22 binds to sialic acid–dependent ligands on human microglia.
• Insulin-like growth factor 2 receptor (IGF2R) was identified as the sCD22 binding partner on human myeloid cells.
• sCD22 binding to IGF2R disrupts lysosomal protein trafficking.
• CD22 blocking antibodies ameliorated lysosome dysfunction in human NPC1 iPSC-derived microglia-like cells without affecting oligodendrocytes.

Conclusions:

• CD22 plays a distinct role in human brain myeloid cells compared to mice.
• The sCD22-IGF2R interaction is a key mechanism driving lysosome dysfunction in human NPC.
• Targeting the sCD22-IGF2R interaction with antibodies represents a potential microglia-directed immunotherapy for Niemann-Pick type C disease.