ER Stress Drives Hyperinflammation via IκBζ-XBP1s Synergy and Regnase-1 Degradation

Inflammatory diseases, such as sepsis and atherosclerosis, are characterized by complex interactions between immune signaling and cellular stress. While endoplasmic reticulum (ER) stress is a known modulator of immunity, the precise mechanisms by which it robustly promotes inflammatory pathology remain incompletely understood. Specifically, NF-κB activation alone, often induced by ER stress, is insufficient to account for the high levels of IL-6 production observed in severe inflammation, suggesting additional regulatory pathways are involved beyond canonical NF-κB activation.

Researchers investigated the mechanisms linking ER stress to amplified inflammatory responses using bone marrow-derived macrophages and sepsis model mice. The study focused on identifying critical mediators of inflammation in the context of ER stress. They explored how ER stress interacts with TLR signaling and examined the roles of specific transcription factors and RNA-binding proteins. Key experimental approaches involved analyzing gene expression, protein accumulation, and the impact of these interactions on inflammatory cytokine production, particularly IL-6, in both cellular and in vivo models.

The study identified the inducible transcription factor IκBζ as a critical mediator of ER stress-amplified inflammation. ER stress was found to synergize with TLR signaling, leading to a marked upregulation of IκBζ. Mechanistically, ER stress triggered calcium-dependent signaling that resulted in IκB kinase-mediated degradation of the RNase Regnase-1. This degradation likely stabilized Nfkbiz mRNA, thereby promoting the accumulation of IκBζ.