Ionizing Radiation Expands p90RSK-Activated Patrolling Monocytes Modulated by Colchicine
Overview
Ionizing radiation selectively expands a subset of patrolling monocytes (CD14−CD16+CD68hi) characterized by elevated p90RSK activation and reduced CHIP-associated proteins DNMT3A and TET2. Colchicine suppresses this radiation-induced expansion without restoring CHIP protein expression, indicating targeted modulation of p90RSK-driven signaling pathways.
Background
Radiation-induced cardiovascular disease (RICVD) is a significant late complication in cancer survivors receiving thoracic radiotherapy, contributing to increased morbidity and mortality. Ionizing radiation causes vascular injury and immune cell remodeling, but the molecular mechanisms, especially involving clonal hematopoiesis-associated proteins and stress signaling in monocytes, are not fully understood. Colchicine, an anti-inflammatory agent proven to reduce cardiovascular events, may influence radiation-induced immune changes, yet its effects on radiation-induced senescence and inflammatory signaling remain underexplored. This study investigates colchicine's modulation of immune cell subsets following ionizing radiation exposure in vitro.
Data Highlights
Condition
Cell Population
p90RSK Activation
DNMT3A Expression
TET2 Expression
Monocyte Subset Expansion
Control
CD14−CD16+CD68hi Monocytes
Baseline
Normal
Normal
Baseline
Ionizing Radiation (2 Gy)
CD14−CD16+CD68hi Monocytes
Elevated
Reduced
Reduced
Significant Expansion
Ionizing Radiation + Colchicine
CD14−CD16+CD68hi Monocytes
Suppressed Expansion
Remains Reduced
Remains Reduced
Suppressed Expansion
Key Findings
Ionizing radiation (2 Gy) does not change overall immune cell frequencies but increases p90RSK activation specifically in CD14−CD16+ monocytes.
The CD14−CD16+CD68hi patrolling monocyte subset shows the highest p90RSK activation and expands significantly after radiation exposure.
Radiation reduces expression of CHIP-associated proteins DNMT3A and TET2 in this monocyte subset.
Colchicine treatment suppresses the radiation-induced expansion of CD14−CD16+CD68hi monocytes without restoring DNMT3A or TET2 levels.
Colchicine selectively modulates p90RSK-driven signaling pathways in patrolling monocytes, distinct from its canonical anti-inflammatory effects.
Clinical Implications
These findings suggest colchicine may mitigate radiation-induced vascular inflammation by targeting a specific monocyte subset with heightened p90RSK activity, potentially reducing cardiovascular risk in cancer survivors. Incorporating colchicine into therapeutic strategies could provide a novel approach to prevent or treat radiation-induced cardiovascular disease by modulating immune remodeling beyond conventional anti-inflammatory mechanisms.
Conclusion
Ionizing radiation promotes expansion of a p90RSK-activated patrolling monocyte subset with reduced CHIP protein expression, a process effectively suppressed by colchicine. This study reveals a novel mechanism by which colchicine may counteract radiation-induced immune alterations, supporting further investigation in clinical settings to reduce cardiovascular complications in cancer survivors.
Related Resources & Content
LoDoCo2 and COLCOT Trials -- Colchicine Reduces Cardiovascular Events
Radiation-Induced Cardiovascular Disease -- Epidemiology and Mechanisms
by Masaki Imanishi, Venkata S. K. Samanthapudi, Nhat-Tu Le, Luis Antonio Rivera, Jung Hyun Kim, Jonghae Lee, Gilbert F. Mejia, Oanh Hoang, Anita Deswal, Keri L. Schadler, Michelle A. T. Hildebrandt, Syed Wamique Yusuf, Guangyu Wang, Jared K. Burks, Roza I. Nurieva, Nicolas L. Palaskas, Kevin T. Nead, El-ad David Amir, Efstratios Koutroumpakis, Steven H. Lin, Jun-ichi Abe, Sivareddy Kotla
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