CLEC16A regulates splenocyte and NK cell function in part through MEK signaling

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• CLEC16A is associated with various autoimmune diseases.
• Its precise role in autoimmunity and inflammation remains unclear.

Purpose of the Study:

• To investigate the functional link between CLEC16A, auto-inflammation, and autoimmunity using inducible knockout mice.
• To explore the impact of CLEC16A deficiency on immune cell function and mitophagy.

Main Methods:

• Generation of Clec16a inducible knockout (KO) mice.
• Analysis of immune cell populations (B, T, NK cells) in KO mice.
• Assessment of mitochondrial function and mitophagy.
• Pharmacological inhibition of PI3K and MEK pathways.

Main Results:

• Clec16a KO mice displayed weight loss, thymic and splenic atrophy.
• Reduced mitochondrial potential and disrupted mitophagy were observed in splenic B and T cells.
• NK cells from KO mice showed increased cytotoxicity.
• Incomplete mitophagy was partially reversed by PI3K/MEK inhibition.

Conclusions:

• CLEC16A plays a crucial role in maintaining mitophagy in immune cells.
• Disrupted mitophagy due to CLEC16A deficiency contributes to inflammation and autoimmune predispositions.
• Targeting mitophagy pathways presents a potential therapeutic avenue for autoimmune diseases associated with CLEC16A variants.