Context-dependent fidelity of damage-induced cytokine bursts across vertebrate regeneration models
July 17
Damage-evoked cytokine bursts are widely viewed as energetically costly, therefore evolutionarily reliable, cues that a tissue genuinely requires reparative resources. Nevertheless, aberrant tissues can co-opt such bursts to attract trophic support—classic decoy signaling. The present work examined the conditions under which cytokine release is interpreted as a faithful call for repair versus a deceptive ploy.
In an initial screen of 7,007 laser-defined wound fields in murine epidermis, simultaneous release of IL-33 and extracellular ATP elevated perceived signal fidelity in resident macrophages, an effect moderated by local oxidative tone and by the epithelial lineage of the damaged cells.
Two principal studies (3,488 independent microenvironments) employed a library of standardized and non-standardized cell mosaics differing in cytokine density. Lesions were embedded in either trophic-rich or trophic-neutral matrices and were engineered to display low or high basal redox tone. Signal fidelity was quantified by calcium influx and migratory orientation in responder phagocytes across five vertebrate systems—Danio, Xenopus, Gallus, Mus, and human ex vivo skin. Main effects were modest: overall, cytokine-rich lesions were rated marginally higher in fidelity (η²<0.02), but outcomes varied with tissue context, lesion genotype, and species.
Stronger fidelity enhancement emerged when lesions possessed a low redox baseline, achieved either by CRISPR ablation of mitochondrial SOD2 or by selecting epithelial lineages naturally low in ROS buffering. This, in turn, amplified fibroblast recruitment and collagen deposition. Trophic-rich surroundings slightly eroded fidelity assessments, yet this erosion interacted with lesion genotype; high-redox lesions were disproportionately discounted.
Responder heterogeneity also mattered. Macrophages bearing a gain-of-function PD-1 variant or high TIM-3 expression assigned consistently lower fidelity scores to cytokine-rich lesions, suggesting that immune personality shapes interpretation of damage cues.
Collectively, our data confirm that the authenticity of damage-induced cytokine bursts rests on a multifactorial landscape encompassing cellular lineage, metabolic state, and evolutionary history. The modest effect sizes highlight the need for more refined perturbations and in situ imaging platforms that better mimic regenerative microenvironments.