JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice

Area of Science:

• Immunology
• Metabolic disease
• Molecular biology

Background:

• CLEC16A is associated with autoimmune diseases.
• The precise physiological roles of CLEC16A remain unclear.

Purpose of the Study:

• To investigate the function of CLEC16A using an inducible whole-body knockout mouse model (Clec16a^ΔUBC).
• To elucidate the mechanistic link between CLEC16A, lipid metabolism, and immune system perturbations.

Main Methods:

• Generation of inducible whole-body knockout (KO) mice (Clec16a^ΔUBC).
• Analysis of metabolic parameters, including adipose tissue, weight, glucose tolerance, insulin levels, and lipid profiles.
• Investigation of autophagic flux, endoplasmic reticulum (ER) stress, and cytokine storm.
• Assessment of signaling pathways including JAK-STAT, stress kinases, and hormone-sensitive lipase (HSL).
• Pharmacological intervention using a JAK-STAT inhibitor (tofacitinib).

Main Results:

• Clec16a^ΔUBC mice exhibited significant weight loss, adipose tissue depletion, defective autophagic flux, and exaggerated ER stress.
• KO mice displayed systemic inflammation, elevated antibody levels, reduced insulin, and altered lipid profiles.
• ER stress-induced lipolysis via HSL activation contributed to adipose inflammation through JAK-STAT and stress kinase pathways.
• Tofacitinib treatment partially ameliorated the inflammatory lipodystrophic phenotype and improved survival by modulating ER stress, lipolysis, and autophagy.

Conclusions:

• CLEC16A plays a critical role in maintaining normal physiology, particularly in regulating lipid metabolism and immune responses.
• Defective CLEC16A function leads to a complex phenotype involving metabolic dysfunction and systemic inflammation.
• Targeting JAK-STAT signaling offers a potential therapeutic strategy for conditions associated with CLEC16A deficiency.