Redox Imbalance in Inflammation: The Interplay of Oxidative and Reductive Stress

Abstract

Redox imbalance plays a pivotal role in the regulation of inflammation, influencing both the onset and progression of various inflammatory conditions. While the pro-inflammatory role of oxidative stress (OS) is well established, the impact of reductive stress (RS)-a condition marked by excessive reducing equivalents such as NADH, NADPH, and reduced glutathione (GSH)-remains underappreciated. This review offers a novel integrative perspective by analyzing how OS and RS act not merely in opposition, but as interconnected modulators of immune function. We explore the mechanisms through which OS activates inflammatory pathways, and how RS, when sustained, can paradoxically impair immune defense, alter redox-sensitive signaling, and contribute to disease progression. Emphasis is placed on the dynamic interplay between these redox extremes and their combined contribution to the pathogenesis of chronic inflammatory diseases, including autoimmune, cardiovascular, and neuroinflammatory disorders. Additionally, we evaluate therapeutic strategies that target redox homeostasis, arguing for a shift from antioxidant-centric treatments to approaches that consider the bidirectional nature of redox dysregulation. This framework may inform the development of more precise interventions for inflammation-related diseases.

Keywords: immune regulation; inflammation; oxidative stress; redox imbalance; reductive stress.

Figure 1

Reactive oxygen species (ROS)-mediated activation of the NF-κB signaling pathway. ROS, either produced endogenously or induced by extracellular stimuli, promote the activation of the IκB kinase (IKK) complex (IKKα, IKKβ, and IKKγ). Activated IKK phosphorylates IκB, the inhibitory subunit of the cytoplasmic NF-κB complex (p50/p65 or p50/c-Rel). ROS has also been shown to activate NF-κB through alternative IκB phosphorylation. Phosphorylated IκB undergoes ubiquitination and subsequent proteasomal degradation, liberating the NF-κB dimer. The released NF-κB translocates into the nucleus, where it binds DNA and activates the transcription of pro-inflammatory and immune response genes. ROS also modulate the DNA binding of NF-κB and amplify transcriptional activity, creating a feed-forward loop in inflammation. Created in https://BioRender.com (accessed on 15 May 2025).

Figure 2

Reductive stress impairs immune cell function and promotes immune dysregulation. An excessively reduced intracellular environment—characterized by elevated GSH/GSSG, NADH/NAD⁺, and NADPH/NADP⁺ ratios—can compromise both innate and adaptive immunity. In macrophages and neutrophils, reductive stress suppresses NADPH oxidase activity, impairing the oxidative burst and microbial killing. Dendritic cells show reduced major histocompatibility complex (MHC)-II and CD86 expression, weakening T cell priming. In T lymphocytes, low ROS availability impairs T cell receptor (TCR) signaling and cytokine release, while B cells exhibit diminished antibody class switching and production. These immunosuppressive effects contribute to increased susceptibility to infections and chronic inflammation. Created in https://BioRender.com (accessed on 15 May 2025).

Figure 3

Redox regulation of immune responses: the continuum between reductive stress, redox homeostasis, and oxidative stress. Under physiological conditions (central panel), a balanced redox environment supports immune function by maintaining appropriate levels of reactive oxygen and nitrogen species (ROS/RNS), such as superoxide (^•O₂⁻), hydroxyl radical (^•OH), nitric oxide (^•NO), and peroxynitrite (ONOO⁻), primarily generated via regulated NOX activity. These species act as signaling molecules in immune activation, microbial killing, and tissue repair. In oxidative stress (right panel), excess ROS/RNS (red color) drive chronic inflammation and tissue injury, contributing to pathologies such as cardiovascular and neuroinflammatory diseases. In contrast, reductive stress (left panel), marked by increased intracellular reducing equivalents (e.g., high NADH/NAD⁺, NADPH/NADP⁺, and GSH/GSSG ratios, green color), leads to suppressed immune activation, impaired pathogen clearance, and dysregulated signaling. This overly reduced state may favor immune tolerance, impair cytokine responses, and promote metabolic dysfunction. The figure highlights the importance of maintaining redox homeostasis for immune integrity and inflammation control. Created in https://BioRender.com (accessed on 25 May 2025).