Deficiency of AP1M2 Causes a New Autoinflammatory Disease With Colitis.

Area of Science:

• Immunology
• Genetics
• Gastroenterology

Background:

• Autoinflammatory diseases involve dysregulated immune responses.
• The specific genetic causes of some autoinflammatory conditions remain unknown.
• Understanding the molecular basis of these diseases is crucial for developing targeted therapies.

Purpose of the Study:

• To identify the genetic cause of a novel autoinflammatory disease characterized by colitis.
• To elucidate the pathogenic mechanisms of AP1M2 deficiency in both mouse models and human patients.
• To investigate the role of AP-1 complex in regulating inflammatory pathways.

Main Methods:

• Genetic analysis of patients to identify causative variants.
• Generation and characterization of Ap1m2-deficient mice.
• Utilizing DLD-1 cells and advanced imaging techniques (Stereo-seq, super-resolution imaging).
• Investigating the interplay between AP1M2 deficiency and TNFR1 signaling.

Main Results:

• A biallelic loss-of-function variant in AP1M2 was identified as the cause of the disease.
• Ap1m2-deficient mice developed spontaneous intestinal inflammation and elevated chemokine production.
• AP1M2 deficiency leads to TNFR1 pathway activation, causing NF-κB activation and chemokine overproduction.
• TNFR1 knockout ameliorated the intestinal inflammation in Ap1m2-deficient mice.

Conclusions:

• AP1M2 deficiency is identified as a novel cause of autoinflammatory disease with colitis.
• AP-1 plays a critical role in suppressing NF-κB activation and chemokine production.
• Targeting the AP-1 or TNFR1 pathways may offer therapeutic strategies for this condition.