Regulation and resolution of innate immune signaling in autoinflammatory disease

Innate immunity, orchestrated by pattern recognition receptors (PRRs) including TLRs, NLRs, and the cGAS–STING pathway, forms the foundation of host defense. While downstream signaling cascades are well characterized, emerging evidence reveals complex regulation through immunometabolism, post-translational modifications, and tissue microenvironment cues. Recent epitranscriptomic advances further show that RNA modifications (e.g., m⁶A and m⁵C methylation) control mRNA export, stability, and translation of innate immune genes. These modifications are dynamically regulated by immune signals and reciprocally shape response intensity and duration. Disruptions in these regulatory networks underlie diverse pathologies, from acute inflammation to chronic metabolic and neurodegenerative diseases. Elucidating the molecular checkpoints that calibrate innate immune activation is therefore essential to understanding how the immune system balances effective defense against destructive autoinflammation.This Research Topic addresses the translational bottleneck in modulating innate immune responses. Despite high-resolution mapping of PRR activation, the mechanisms governing signal resolution and termination remain underexplored. The fundamental challenge is selectively attenuating pathological hyper-inflammation without compromising essential host defense. Recent advances highlight regulatory "rheostats"—post-translational modifications, metabolic checkpoints, and epitranscriptomic mechanisms—that control signaling magnitude and duration. RNA modifications such as m⁶A and m⁵C methylation have emerged as critical regulators of innate immunity, controlling the fate of mRNAs encoding inflammatory mediators and feedback regulators. However, how these modifications coordinate with innate immune signaling and contribute to signal termination remains incompletely understood. By interrogating how autophagy and ER stress intersect with NLRP3 or cGAS-STING sensor stability, and how epitranscriptomic regulation interfaces with these events, we can define the molecular boundaries of the "window of resolution." This collection aims to synthesize these mechanistic insights to uncover novel druggable nodes. Ultimately, we aim to leverage these regulatory paradigms to develop next-generation immunotherapies that precisely recalibrate innate immunity in chronic metabolic and autoinflammatory diseases.• Biochemical Regulation: Elucidating the role of post-translational modifications—including ubiquitination, phosphorylation, and SUMOylation—in the spatiotemporal control of PRR signaling.• ·Epitranscriptomic Regulation: Investigating the role of RNA modifications (e.g., m⁶A and m⁵C methylation) in innate immunity, including how they regulate mRNA nuclear export, stability, and translational efficiency, as well as how these modifications are modulated by innate immune signals and, in turn, reciprocally regulate innate immune responses.• Immunometabolism: Investigating how cellular metabolic states and nutrient sensing dictate innate immune phenotypes and effector functions.• Signaling and Cell Death: Exploring the molecular crosstalk between pyroptosis, autophagy, and inflammatory resolution.• Pathophysiological Contexts: The role of innate sensors in driving chronic metabolic dysregulation (e.g., MAFLD) and neurodegenerative disorders.• Therapeutic Frontiers: Development of innovative small molecules or biologics targeting specific regulatory "checkpoints" to recalibrate immune responses. Topic editors: Li Zhou, Jinbiao Liu, Lina Zhou Source: https://www.frontiersin.org/research-topics/79654/regulation-and-resolution-of-innate-immune-signaling-in-autoinflammatory-disease