Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Nucleophosmin 1 (NPM1) mutations are common in myeloid malignancies.
• Inflammatory bowel diseases (IBD) and myelodysplastic syndrome (MDS) often co-occur.
• The role of NPM1 in IBD and colitis-associated cancer (CAC) is not well understood.

Purpose of the Study:

• To investigate the function of NPM1 in IBD and CAC.
• To elucidate the molecular mechanisms by which NPM1 influences IBD pathogenesis.

Main Methods:

• Analysis of NPM1 expression in IBD patients.
• Utilizing Npm1 heterozygous knockout mice and ILC3-specific Npm1 knockout mice.
• Assessing susceptibility to acute colitis and experimentally induced CAC.
• Investigating the impact of Npm1 deficiency on interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s) function, mitochondrial metabolism, and the p65-TFAM axis.

Main Results:

• NPM1 expression was reduced in IBD patients.
• Npm1 deficiency increased susceptibility to colitis and CAC in mice.
• Npm1 deficiency impaired ILC3 function, reducing IL-22 production and accelerating colitis.
• NPM1 is crucial for mitochondrial biogenesis and oxidative phosphorylation in ILC3s.
• NPM1 cooperates with p65 to promote TFAM transcription in ILC3s.
• Overexpression of Npm1 enhanced ILC3 function and ameliorated colitis severity.

Conclusions:

• NPM1 in ILC3s plays a protective role against IBD.
• NPM1 regulates IBD pathogenesis by controlling mitochondrial metabolism via the p65-TFAM pathway in ILC3s.