Th17 development and autoimmune arthritis in the absence of reactive oxygen species

Abstract

Dendritic cells (DC) express a functional NADPH oxidase and produce reactive oxygen species (ROS) upon interaction with microbes and T cells. Exposure to ROS leads to DC activation and maturation, as evidenced by phenotypic and functional changes. We have evaluated how endogenous ROS production affects the cytokine secretion pattern and T cell-activating capacity of bone marrow-derived murine DC. DC treated with ROS scavengers, as well as DC from mice that lack a functional NADPH oxidase (and thereby inherently deficient in ROS production) produced significantly increased levels of IL-1b, IL-6, TNF-a and TGF-b in response to microbial activation. DC deficient in ROS production induced high levels of IFN-c and IL-17 in responding T cells after Ag-specific or superantigen-induced activation. Finally, we show that ROS deficiency affected the induction of a T cell-dependent inflammatory condition, collagen-induced arthritis (CIA). C57BL/6 mice that lack a functional NADPH oxidase developed a severe and erosive CD4-dependent CIA, whereas the majority of the congenic wild-type animals remained healthy. These data suggest that ROS act as immunomodulators in DC-driven T cell activation and perhaps also in T cell-dependent immunopathology.Key words: CD4 + T cells Á Cytokines Á Dendritic cells Á Immune regulation Á Rheumatology IntroductionImmature myeloid DC reside in non-lymphoid organs and sense the environment through the expression of a panel of patternrecognition receptors. In the immature stage, DC have a high capacity to ingest foreign Ag but they express low levels of molecules that are involved in T cell activation. Once activated through one or several pattern recognition receptors, the DC undergo phenotypic and functional changes that involve migration to a lymphoid organ, reduced ability to sample Ag, and enhanced expression and secretion of molecules that attract and activate naive T cells. Thus, both the localization of DC and the capacity of DC to activate T cells are maturation dependent. Depending on the nature of the activating stimuli and the signaling properties of the pattern-recognition receptors involved, the DC acquire certain traits that affect the quality of the ensuing T cell response. The best known example is the development of Th1 and Th2 responses, which depend to a large extent on the cytokine secretion profile induced in the DC (reviewed in [1]). Consequently, factors that affect the maturation of DC influence the subsequent T cell profile.ROS represent endogenous factors that may influence the function of DC. ROS induce both DC maturation [2, 3] and the synthesis of pro-inflammatory cytokines [4]. Conversely, antioxidants block DC maturation [5]. DC have all the components of a functional NADPH oxidase within their plasma membranes [6], and produce ROS in response to both cognate T cell interactions [7] and microbial components [8,9]. Thus, ROS could serve as endocrine regulators of DC function and thereby influence the nature of the ensuing immune response. There is evidence that ROS c...

Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species

“…Upon potent immune activation (e.g., efficient antigen presentation by DC), the immune-suppressive effect of Mph may be overwhelmed. This hypothesis is in line with the observation that both patients with CGD and mice with a nonfunctional Nox2 are more prone to develop autoimmunity (8,10,44,29,45). This observation suggests that Mphderived ROS may protect against (auto-)immune activation.…”

Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells

“…Interestingly, mice lacking p47 phox or gp91 phox were lethally susceptible to microbial infection, developed granulomatous inflammation similar to symptoms in human CGD patients (9,10), and demonstrated intensified chondrocyte destruction and joint inflammation in an experimental arthritis model (11)(12)(13). Inactivation of p22 phox also resulted in clinically CGD-like immune defects in mice due to the inability of phagocytes to produce bacteria-killing ROS (14).…”

“…Imbalance between Th1/Th17 and Treg cells is closely associated with autoimmune disease. Previous studies of NOX2-deficient mice have reported increased arthritis development and enhanced Th17 and IFN-γ production, but only upon stimulation with chicken type 2 collagen (CII) and complete Freund's adjuvant (CFA), and found evidence that NOX2-deficient dendritic cells produced higher levels of TGF-β and IL-6 than WT cells, thus resulting in enhanced TH17 development in NOX2 KO mice (11,13). However, the effects of NOX2 deficiency on intrinsic IL-17 production between WT and KO T cells have not yet been determined.…”

Hyperbaric Oxygen Therapy (HBOT) as a Therapeutic Option for Patients with Atopic Dermatitis (AD) – Own Experiences and Literature Review

“…Although traditionally reactive oxygen species are linked with the progression of inflammatory diseases, it is currently known that elevated ROS levels in tissues due to hyperbaric oxygen therapy with simultaneous presence of immunomodulating molecules indoleamine-2,3-dioxygenase (IDO) and hypoxiainducible factor 1α (HIF-1α), has a key effect on the function and differentiation of T regulatory cells (Tregs) [54,55,56,57].…”

“…These cells -depending on current ROS tissue status and expression of one of the regulatory moleculesmay differentiate in two directions: FoxP3 + Tregs (in the case of IDO expression) or TH17 (in the case of HIF-1α expression), where an advantage of differentiation in one direction results in the simultaneous inhibition of differentiation in the opposite direction [14,54,55,58,59]. These are important observations, considering the studies conducted by Faleo et al, who found that FoxP3 + Tregs may be involved in the mechanism of preventive effect of HBOT in an animal model (NOD mice) of autoimmune diabetes [21].…”