Lupus-like autoimmune disease caused by a lack of Xkr8, a caspase-dependent phospholipid scramblase

Area of Science:

• Cell Biology
• Immunology
• Molecular Biology

Background:

• Apoptotic cells signal for clearance by exposing phosphatidylserine (PtdSer).
• Xkr8 is a caspase-dependent scramblase that mediates PtdSer exposure.

Purpose of the Study:

• To investigate the role of Xkr8 in apoptotic cell clearance in mouse hematopoietic cells.
• To determine the consequences of Xkr8 deficiency on immune cell homeostasis and autoimmune disease development.

Main Methods:

• Utilized knockout mouse models (Xkr8-deficient mice).
• Assessed phosphatidylserine exposure on apoptotic thymocytes, splenocytes, and neutrophils.
• Evaluated phagocytosis of apoptotic cells by macrophages in vitro.
• Quantified apoptotic and senescent neutrophils in vivo.
• Analyzed immune cell populations, autoantibody production, and glomerulonephritis in Xkr8-null mice on an MRL background.

Main Results:

• Mouse hematopoietic cells primarily express Xkr8 among caspase-dependent scramblases.
• Xkr8 deficiency significantly reduced PtdSer exposure on apoptotic lymphocytes and neutrophils.
• Phagocytosis of Xkr8-deficient apoptotic cells by macrophages was impaired.
• Accumulation of apoptotic thymocytes and neutrophils was observed in Xkr8-deficient mice.
• Xkr8-null mice developed lupus-like autoimmune disease, including autoantibodies, splenomegaly, and glomerulonephritis.

Conclusions:

• Xkr8-mediated PtdSer exposure is essential for the clearance of apoptotic lymphocytes and aged neutrophils.
• Defects in Xkr8 function lead to impaired apoptotic cell clearance and trigger autoimmune responses.
• Xkr8 deficiency can result in the development of lupus-like autoimmune conditions.