Tet2 restrains inflammatory gene expression in macrophages

Area of Science:

• Immunology
• Epigenetics
• Hematology

Background:

• Tet methylcytosine dioxygenase 2 (TET2) mutations are frequent in clonal hematopoiesis and myeloid cancers.
• TET2 regulates DNA demethylation and gene transcription.
• Inactivating TET2 mutations lead to epigenetic dysregulation and stem cell expansion.

Purpose of the Study:

• Investigate the role of Tet2 in macrophage (MΦ) differentiation and inflammatory responses.
• Determine the impact of Tet2 loss on MΦs in vitro and in vivo.
• Examine TET2 mutations in MΦs from myeloid cancer patients.

Main Methods:

• Assessed Tet2 expression during murine MΦ differentiation.
• Stimulated bone-marrow-derived MΦs (BMMΦs) with lipopolysaccharide (LPS) or interleukin-4 (IL-4).
• Analyzed gene expression in Tet2-deficient MΦs and peritoneal MΦs in vivo.
• Detected TET2 mutations in patient-derived BMMΦs.

Main Results:

• Tet2 expression is induced by LPS in MΦs.
• Tet2 loss increases pro-inflammatory gene expression (Il-1b, Il-6, Arg1) at later stages of LPS stimulation.
• Tet2-deficient MΦs exhibit constitutive expression of LPS-induced inflammatory genes in vivo.
• Tet2 deficiency does not significantly affect alternative MΦ gene expression upon IL-4 stimulation.
• Detected TET2 mutations in BMMΦs from MDS and CMML patients.

Conclusions:

• Tet2 restrains inflammation in murine MΦs and mice, suggesting impaired resolution of inflammation upon Tet2 loss.
• TET2 mutations in MΦs may alter the immune environment in patients with TET2-mutant CHIP and myeloid cancers.