Computational Modelling of Cell‑cycle Dynamics and Innate Immune Signalling in Different Radiation Environments
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The interaction between radiation and the immune system is a hot topic of research, with complex and contradictory results and significant clinical potential. Low-dose radiation exposures have been shown to affect both innate and adaptive immunity, inducing a dynamic balance between pro- and anti-inflammatory effects, highly dependent on the physiological context. Natural background radiation has been a ubiquitous stress factor in the evolution of living organisms. Presumably, removing this factor would lead to an altered maintenance of cellular homeostasis and immune competence. Deep underground laboratories offer the chance of performing radiobiological measurements in below-background radiation environments. The INFN-funded DISCOVER22 project investigated the innate immune response modulation at Laboratori Nazionali del Gran Sasso (Italy). Radiobiological experiments on cells cultured in low-radiation environment (LRE) compared to a reference-radiation environment (RRE) have shown a down-regulation of innate immunity in HaCaT cells (human keratinocytes) exposed to a 1Gy X-ray challenging dose. To interpret experimental findings and gain mechanistic insights, we developed a deterministic compartmental model based on ODEs to describe the population dynamics of irradiated HaCaT cells after adaptation to LRE or RRE. The model includes compartments for interphase, mitosis, radiation‑induced cell death, and a sequence of stages describing the formation and evolution of micronuclei (MN) as markers of genomic instability, and the probability and temporal kinetics of cGAS recruitment when MN rupture and release cytosolic DNA activating innate immune signalling. Time‑dependent transition rates encode radiation‑induced perturbations of cell‑cycle progression and DNA damage processing. Experimental inputs consist of growth curves, flow-cytometry measurements of phase distributions, micronucleus yields and cGAS-STING activation, at multiple post‑irradiation times under both radiation conditions. Overall, the proposed modelling framework integrates mechanistic ODE‑based population dynamics with multivariate experimental data to quantify immune modulation in below‑background radiation. By establishing how radiation‑dependent changes in cell‑cycle, micronuclei dynamics, and cGAS–STING signalling emerge already in healthy cell systems, it provides a quantitative basis which could be extended to tumour models and for informing future radioimmunotherapy strategies.
