Role of redox signaling in neuroinflammation and neurodegenerative diseases

Abstract

Reactive oxygen species (ROS), a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS) have been detected in patients with neurodegenerative diseases such as Alzheimer's disease (AD). These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs), cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases.

Figure 1

Schematic presentation of the interaction of the brain cells, including neurons and glial cells. In the central nervous system (CNS), proinflammatory factors induce the expression of various inflammatory mediators in neuroglial cells, particularly microglia and astrocytes. These induced inflammatory mediators from glial cells may cause the neuroinflammation or neuronal death, and then leading to neurodegenerative disorders.

Figure 2

Oxidative stress and antioxidants imbalance in inflammation. In inflammation, the balance appears to be tipped in favor of increased oxidative stress by various specialized enzymes, including Nox, Xox, P450, COX, or NOS, either because of excessive ROS release or inflammatory mediators leading to the amplification of the proinflammatory effects. In contrast, induction of several antioxidants, such as SOD, catalase, GPx, thioredoxin, or HO-1, may reduce ROS generation and attenuate the inflammatory response (anti-inflammation). Nox: NADPH oxidase; Xox: Xanthine oxidase; P450: P450 enzyme; COX: cyclooxygenase; NOS: nitric oxide synthase; SOD: superoxide dismutase; GPx: glutathione peroxidase; HO-1: heme oxygenase-1.

Figure 3

Major pathways of reactive oxygen (nitrogen) species generation and metabolism. Several proinflammatory factors can stimulate O₂ ^∙− generation through activation of several specialized enzymes, such as the Nox, Xox, P450, COX, or NOS. SOD then converts the O₂ ^∙− to H₂O₂, which is then converted into the highly reactive ^∙OH or has to be rapidly removed from the system that is generally achieved by catalase or peroxidases, such as the GPx. Further, O₂ ^∙− can be either converted into ROO^∙ or can react with NO to yield ONOO⁻. NO is mostly generated by L-Arg via NOS. H₂O₂ can be converted to HOCl by the action of MPO. myeloperoxidase. O₂: molecular oxygen; H₂O: water; O₂ ^∙−: superoxide radical anion; ^∙OH: hydroxyl radical; ROO^∙: peroxyl radical; H₂O₂: hydrogen peroxide; ONOO⁻: peroxynitrite; NO: nitric oxide; L-Arg: L-arginine; HOCl: hypochlorous acid.

Figure 4

Schematic representation of the redox signals (ROS production) and their role in the development of neuroinflammation and neuronal death. Many of the well-known inflammatory target proteins, such as MMP-9, ICAM-1, VCAM-1, COX-2, and cPLA₂, can be upregulated by various proinflammatory factors, including cytokines, peptides, bacterial or viral infection, peroxidants, via a ROS signal-dependent manner in neuroglial cells. These inflammatory mediators can cause neuroinflammation and neuronal death. IL-1β: interleukin-1β; TNF-α: tumor necrosis factor-α; BK: bradykinin; ET-1: endothelin-1; Aβ: β-amyloid; oxLDL: oxidized low-density lipoprotein; H₂O₂: hydrogen peroxide; TGF-β: transforming growth factor-β; MMP-9: matrix metalloproteinase-9; cPLA₂: cytosolic phospholipase A₂; COX-2: cyclooxygenase-2; iNOS: inducible nitric oxide synthase; ICAM: intercellular adhesion.

Figure 5

Proposed mechanisms of proinflammatory factors-stimulated activation of various signaling molecules and transcription factors leading to the expression of inflammatory target genes in brain resident cells. The intracellular signaling molecules include ROS, EGFR/PDFER, PI3K/Akt, and MAPKs. Oxidative stress may regulate these signaling pathways leading to activation of transcription factors such as NF-κB and AP-1 and recruitment of coactivator p300 in the transcription initiation complex. Ultimately, upregulation of diverse inflammatory target proteins can cause the pathogenesis of several neurodegenerative diseases. EGFR: epidermal growth factor receptor; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide-3′-kinase; MAPKs: mitogen-activated protein kinases; NF-κB: Nuclear factor-κB; AP-1: activator protein-1.