Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression

Abstract

Heme oxygenase-1 (HO-1) is an intracellular enzyme that degrades heme and inhibits immune responses and inflammation in vivo. In most cell types, HO-1 is inducible by inflammatory stimuli and oxidative stress. Here we demonstrate that human monocyte-derived immature dendritic cells (iDCs) and several but not all freshly isolated rat splenic DC subsets and rat bone marrow-derived iDCs, spontaneously express HO-1. HO-1 expression drastically decreases during human and rat DC maturation induced in vitro. In IntroductionHeme oxygenases (HOs) are the rate-limiting intracellular enzymes that degrade heme to biliverdin, free divalent iron, and CO (for a review, see Otterbein and Choi 1 ). Three distinct HO enzymes have been identified: HO-1, HO-2, and HO-3. 1 HO-1 is a stress responsive gene whose expression is induced by a variety of stimuli including heme, heavy metals, inflammatory cytokines, and nitric oxide. 1 HO-1 is known for its cytoprotective effect against oxidative injuries and inflammation. 1 Induction of HO-1 expression by pharmacologic activators or gene transfer has had therapeutic effects in a variety of conditions or disorders involving the immune system, including transplantation and inflammatory disorders. [2][3][4][5][6][7][8] Biliverdin and its metabolite, bilirubin, are known for their antioxidant 9 and immunosuppressive effects. 10 HO-1 and CO have been shown to inhibit lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and to increase LPS-induced expression of interleukin 10 (IL-10) in macrophages. 11,12 Moreover, IL-10 induces HO-1 expression in macrophages. [13][14][15] We previously reported that overexpression of HO-1, obtained with an HO-1-encoding adenovirus in rats having heart transplants, results in long-term allograft survival associated with an inhibition of cellular allogeneic immune responses, which could be mediated by adenoviral transduction of dendritic cells (DCs). 6 DCs play a central role in the induction of immunity and tolerance (for a review, see Steinman et al 16 ). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues specialize in taking up innocuous and cell-associated self antigens.They continuously capture antigens and migrate to draining lymph nodes where they can induce tolerance. 16 In the presence of danger signals, DCs undergo maturation, a process involving upregulation of surface major histocompatibility complex (MHC) class II and costimulatory molecules, secretion of proinflammatory and anti-inflammatory cytokines, and the acquired ability to stimulate differentiation of naive T cells into effector cells.Our working hypothesis was that DCs can express HO-1, which can regulate DC functions. In this study, we demonstrate that human and rat iDCs express HO-1 and that HO-1 expression is down-regulated by maturation stimuli. Our results also demonstrate that induction of HO-1 expression renders DCs refractory to LPS-induced maturation, but preserves IL-10 secretion, suggesting that HO-1 may be used to regulate DC f...

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…4). Differential expression of HO-1 among splenic DC subsets has also been confirmed in the rat (39). The CD8 + DC population is depleted in HO-1 deficient mice, while the CD4 + CD8 -subset is not affected (Fig.…”

“…These changes enable mature DC to activate antigen-specific naïve T cells to differentiate into adaptive immune effector cells (29). The expression of HO-1 in DC correlates with their maturity, suggesting that HO-1 may regulate DC maturation, and therefore, downstream adaptive immune responses (Table 2) (39).…”

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

“…HO-1 can modulate the immune response by inhibiting maturation of dendritic cells and by regulating the functions of Th1 and Treg cells [11][12][13]. To investigate whether the protective effect of transgenic mHo-1 works through these immunoregulatory functions, the mHo-1-transgenic NOD mice were crossed with T1/T2 double transgenic NOD mice to generate T1/T2/mHo-1 triple transgenic NOD mice.…”

“…Thus, immature dendritic cells (iDCs) spontaneously produce HO-1, which is downregulated by maturation stimuli such as lipopolysaccharide. Induction of HO-1 production rendered iDCs refractory to lipopolysaccharide-induced maturation, but preserved IL-10 secretion, suggesting that HO-1 plays an important role in the maturation and function of iDCs, and could be used to modulate the immune response [11]. Splenocytes from Ho-1 (also known as Hmox1) knockout mice secreted disproportionately high levels of Th1 cell-associated and proinflammatory cytokines on stimulation, implying a critical regulatory role of HO-1 in Th1/Th2 balance and early inflammatory responses [12].…”

Immunoregulatory Effects of Stored Red Blood Cells

“…17 HO-1 is considered immunosuppressive because it was shown to block the maturation of dendritic cells and to inhibit proinflammatory and allogeneic immune responses. 18,19 Dendritic cells treated with HO-1 and CO can inhibit ROS and the production of proinflammatory cytokines such as IL-12, IL-6, TNF-␣, and IFN type I. 19,20 Conversely, the antiinflammatory IL-10 cytokine is increased after HO-1 overexpression or CO, and CO alone has been shown to inhibit T-lymphocyte proliferation.…”