Redox regulation of the immune response

Abstract

Reactive oxygen and nitrogen species (ROS-RNS) and other redox active molecules fulfill key functions in immunity. Beside the initiation of cytocidal reactions within the pathogen defense strategy, redox reactions trigger and shape the immune response and are further involved in termination and initialization of cellular restorative processes. Regulatory mechanisms provided by redox-activated signaling events guarantee the correct spatial and temporal proceeding of immunological processes, and continued imbalances in redox homeostasis lead to crucial failures of control mechanisms, thus promoting the development of pathological conditions. Interferon-gamma is the most potent inducer of ROS-RNS formation in target cells like macrophages. Immune-regulatory pathways such as tryptophan breakdown via indoleamine 2,3-dioxygenase and neopterin production by GTP-cyclohydrolase-I are initiated during T helper cell type 1 (Th1-type) immune response concomitant to the production of ROS-RNS by immunocompetent cells. Therefore, increased neopterin production and tryptophan breakdown is representative of an activated cellular immune system and can be used for the in vivo and in vitro monitoring of oxidative stress. In parallel, the activation of the redox-sensitive transcription factor nuclear factor-kappa B is a central element in immunity leading to cell type and stimulus-specific expression of responsive genes. Furthermore, T cell activation and proliferation are strongly dependent on the redox potential of the extracellular microenvironment. T cell commitment to Th1, Th2, regulatory T cell, and other phenotypes appears to crucially depend on the activation of redox-sensitive signaling cascades, where oxidative conditions support Th1 development while 'antioxidative' stress leads to a shift to allergic Th2-type immune responses.

Altered Redox Regulation as Cofactor in Comorbidities and Accelerated Aging in HIV Infection Evolution and Antiretroviral Treatment

“…That chronic innate immune activation suppresses functional T cellmediated adaptive immune responses while sustaining the activated phenotype of T cells with disruption of lymphoid architecture and multifactorial immune suppression, including decreased CD4 and CD8 T cells [14,25,26], which resembles many of the alterations observed during HIV infection.…”

“…Those signaling responses subsequently stimulate pathways related to cell senescence and death [42,43]. At the cellular level, ROS have been found to modulate various signals leading to accelerated mitogenesis and premature cellular senescence [25,28]. An additional theory that has gained more attention in recent years is molecular inflammatory theory of aging, whereby activation of redox-sensitive transcriptional factors by age-related OS causes the upregulation of proinflammatory genes expression.…”

“…The immune system of very old individual (>70 years of age) is characterized by increased population of terminally differentiated CD8+ cells effector (which appear to be resistant to apoptosis), reduced levels of naive CD8+ cells, a reversed ratio of CD4+ to CD8+ cells, increased T-cell activation, increased levels of many inflammatory markers, and reduced T-cell proliferation. Most of those outcomes are accelerated by the presence of chronic persistent infections [8,25,36,37].…”

“…Transient over production of ROS in viral infections is generally related to pro-oxidant effect of inflammatory cytokines and/or polymorphonuclear leukocyte activation exerting also intracellular signal transduction cascades within cells and thereby upregulating the cellular response. In regulatory mode, it also contributes to decrease the cell activation threshold [25,26].…”

“…Markers of bacterial translocation, such as lipopolysaccharide, and of innate immunity activation, such as sCD14, together with indications of elevated immune activation, have been linked to neurocognitive and cardiovascular comorbidities and to mortality [14,25,35,44].…”