The unfolded protein response as a proteotoxic stress-resolution circuit: branch-selective signaling and failed...

Environmental immunotoxicity is commonly framed through oxidative stress, cytotoxicity, inflammation, receptor-mediated signaling and cell- or tissue-specific mechanisms. This review proposes that proteotoxic stress resolution represents an additional layer linking environmental exposure to immune dysfunction. Specifically, the unfolded protein response (UPR) is considered as a branch-selective proteotoxic stress-resolution circuit that can shape immune outcomes when endoplasmic reticulum (ER) homeostasis is perturbed. The framework is offered as a hypothesis-generating conceptual structure rather than an established mechanistic paradigm, and the causal step linking failed resolution to immune dysfunction remains largely extrapolated from non-toxicological ER-stress models. Evidence from ER proteostasis biology, immune-cell function and toxicology indicates that environmental toxicants can disrupt protein folding, ER calcium balance, redox homeostasis, lipid composition, degradation pathways and secretory load, thereby engaging distinct combinations of IRE1α, PERK and ATF6 signaling. These branches generate immune-relevant outputs: IRE1α links ER stress to RNA processing and inflammatory signaling, PERK controls translational suppression and fate selection, and ATF6 supports restoration of folding capacity and secretory competence. Across macrophages, dendritic cells, T cells, plasma cells and barrier epithelial cells, immune outcomes depend on branch bias, signaling duration, cell-type context and resolution through ER-associated degradation, autophagy, ER-phagy, translational recovery and restoration of calcium and redox balance. This framework predicts that repeated low-dose exposures, mixed toxicant inputs and incomplete post-exposure recovery can shift immune or barrier cells into inflammatory, suppressive or barrier-disruptive states without overt cytotoxicity. It also supports time-resolved, branch-specific and cell-specific profiling for immunotoxic risk assessment.