Ionizing radiation expands a p90RSK-activated patrolling monocyte subset: modulation by colchicine

Area of Science:

• Immunology
• Molecular Biology
• Radiation Oncology

Background:

• Ionizing radiation (IR) causes vascular injury and immune cell dysfunction.
• Mechanisms involving clonal hematopoiesis proteins and stress pathways in monocytes are unclear.
• The role of DNMT3A and TET2 in radiation-induced monocyte changes requires further investigation.

Purpose of the Study:

• To investigate the effects of IR and colchicine on monocyte subsets.
• To elucidate the role of clonal hematopoiesis-associated proteins (DNMT3A, TET2) and p90RSK signaling in IR-exposed monocytes.
• To determine if colchicine can mitigate IR-induced immune alterations.

Main Methods:

• Peripheral blood mononuclear cells (PBMCs) were treated with colchicine and exposed to 2 Gy IR.
• Mass cytometry (CyTOF) was used with a comprehensive antibody panel.
• Data analysis involved Astrolabe platform for immune subset annotation.

Main Results:

• IR did not alter overall immune cell frequency, but colchicine increased myeloid and B cells.
• IR enhanced p90RSK activation in CD14-CD16+ monocytes, reducing proliferation and inflammatory markers.
• IR decreased DNMT3A and TET2 expression, correlating with elevated p90RSK in CD14-CD16+CD68hi monocytes, which expanded post-IR.
• Colchicine suppressed this expansion without restoring DNMT3A/TET2, indicating selective p90RSK pathway modulation.

Conclusions:

• Colchicine selectively inhibits the expansion of CD14-CD16+CD68hi monocytes, characterized by reduced CHIP proteins and heightened p90RSK.
• This suggests colchicine modulates radiation-responsive monocyte signaling.
• Findings support a hypothesis that colchicine may mitigate radiation-induced vascular inflammation and cardiovascular risk.