Inhibition of Dendritic Cell Maturation and Function Is Independent of Heme Oxygenase 1 but Requires the Activation of STAT3

Mashreghi, Mir‐Farzin; Klemz, Roman; Knosalla, Isabela Schmitt; Gerstmayer, Bernhard; Janßen, Uwe; Buelow, Roland; Józkowicz, Alicja; Dulak, Józef; Volk, Hans‐Dieter; Kotsch, Katja

doi:10.4049/jimmunol.180.12.7919

Cited by 36 publications

(39 citation statements)

References 51 publications

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“…It has recently been described that DCs treated with CoPP up-regulate HO-1 and Stat-3 and that is the last molecule, the one responsible for the effect of CoPP using mouse DCs, but unfortunately this point was not analyzed using human and rat DCs and therefore it is difficult to conclude definitively (47). We confirmed the results obtained with CoPP in human but also mouse DCs using HO-1 gene transfer and other groups did it in DCs using gene transfer of HO-1 (21) or HO-1-deficient mice (12).…”

Section: Discussionmentioning

confidence: 92%

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

Remy

Blancou

Tesson

et al. 2009

The Journal of Immunology

114

131

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Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe 2؉ , and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocytederived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. H eme oxygenases are the rate-limiting enzymes in the catabolism of heme, yielding equimolar amounts or carbon monoxide (CO), 5 free iron, and biliverdin (BV) (1), which is subsequently reduced into bilirubin (BL). Heme oxygenase 1 (HO-1), the inducible form of heme oxygenases, has protective effects in a variety of experimental inflammatory models (reviewed in Ref.2). The physiological importance of HO-1 has been demonstrated in both mice and humans, where HO-1 deficiency resulted in a progressive and chronic inflammation and a reduced cellular resistance to oxidative stress (3-5). Induction of HO-1 expression by pharmacological activators or gene transfer have therapeutic effects in a variety of conditions or disorders involving inflammation and immune responses, including organ transplantation and autoimmunity (6 -12). In several models, CO mimics the effects of HO-1 (reviewed in Ref. 13), indicating that HO-1 acts via the generation of CO. However, other end products of HO-1 activity, such as BV (14), free iron depletion by increased H chain ferritin expression (15), or cellular efflux pumps (16), or heme depletion (17) can also mediate the effects of HO-1.Dendritic cells (DCs) play a major role in the initiation and regulation of the immune response. They have distinct stages of cell development, activation, and maturation and have the potential to induce both immunity and tolerance (reviewed in Ref. 18). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues continuously capture innocuous and cell-associated self-Ags and migrate to draining lymph nodes where they can induce tolerance (19). In the presence of danger and TLR signals, DCs mature, acquiring the ability to stimulate differentiation of naive T cells into effector cells. In certain conditions, phenotypically mature DCs have tolerogenic functions (18).We previously showed that human and rat iDCs express HO-1, that this expression is restricted to certain DC populations, and that HO-1 expression drastically decreases upon DC maturation (20). We and others have demonstrated that overexpression of HO-1 in DCs inhibits their LPS-induced maturation and proinflammatory functions (20,21), and it has been recently...

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Section: Discussionmentioning

confidence: 92%

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

Remy

Blancou

Tesson

et al. 2009

The Journal of Immunology

114

131

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“…20 In our experiments, we could not detect an effect of HO1 deletion on DC maturation, as maturation marker expression of CD40, CD80, and CD86 remained unaffected. Conforming to our findings, Mashreghi et al demonstrated using a knockdown approach that DC maturation was independent of HO1 regulation, 21 and Soares and colleagues 22 showed a lack of response in CD40, CD80, ϩ or CD8 ϩ cells was corrected for the total allograft surface area (m 2 ) and is shown as a percentage of total area. Representative sections of arterial allografts obtained from both ZnPPIX and control groups are shown (magnification: ϫ100).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1

Cheng

Noorderloos

Deel

et al. 2010

Circulation Research

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Key Words: heme oxygenase 1 Ⅲ transplantation arteriosclerosis Ⅲ dendritic cells Ⅲ CD4 ϩ T cell response A rterial intimal hyperplasia subsequent to organ transplantation, ie, transplant arteriosclerosis, continues to impede the long-term allograft survival and patency of vascular allografts. 1 Transplant arteriosclerosis is thought to be initiated by alloimmune-mediated injury to graft endothelial lining of the vascular bed, resulting in endothelial cell activation, and dysfunction, facilitating perivascular infiltration of lymphocytes. Subsequently, intimal vascular smooth muscle cells (VSMCs) respond through activation, migration into the intima of the vessel, followed by cell proliferation and extracellular matrix deposition, which results in progressive neointimal hyperplasia with impediment of allograft perfusion, and eventual graft failure. Alloantigen presentation by host dendritic cells (DCs) initiates the development of an antialloantigen-specific adaptive immune response. 1 Although involvement of DCs in allograft rejection is presumed, the direct function of DCs in the pathogenesis of transplantation arteriosclerosis still remains to be elucidated. Allograft vasculopathy in humans as well as in rodent experimental models is associated with intragraft expression of a series of cytoprotective genes, including the cytokine interleukin (IL)-10 and antiapoptotic gene A20, as well as Heme oxygenase 1 (HO1). 2,3 The latter has previously been associated with an improved survival of the vascular allograft in rat models in response to pharmaceutical induction of HO1. 2,4 HO1 is a stress inducible enzyme that catalyzes the degradation of heme proteins into free iron, CO, and biliverdin, which is then rapidly converted into bilirubin. These catabolic end products exert antioxidant, antiapoptotic, and immune-modulating properties, rendering the overall function of HO1 to be cytoprotective. 5,6 We sought to define the role of HO1 in the genetic regulation of the alloimmune response directed by DCs in transplantation arteriosclerosis. The present study indicates that HO1 in DCs, beside its catabolic and antioxidative Original

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“…The literature on the role of HO-1 in immune signaling pathways is complex because of the variety of experimental systems used, the ability of nearly all cells to make HO-1 under certain conditions, the dependence of certain observations on substrate availability, and because pharmacologic modulators of HO-1 expression are not entirely specific (105). However, consistent themes have emerged indicating a role for HO-1 in inflammatory responses.…”

Section: The Mononuclear Phagocyte Systemmentioning

confidence: 98%

“…In many of the studies that have examined the correlation between DC maturation and HO-1 expression, CoPP was used to pharmacologically upregulate HO-1 activity (Table 2). Mashreghi and colleagues showed that when BMDC are treated with CoPP, inhibition of DC maturation is not dependent on HO-1 expression (105). BMDC generated from HO-1-deficient mice or treated with HO-1-specific siRNA were prevented from LPS-induced maturation when treated with CoPP.…”

Section: Role Of Ho-1 In the Mononuclear Phagocyte Systemmentioning

confidence: 99%

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

Hull

Agarwal

George

2014

Antioxidants & Redox Signaling

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Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

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Inhibition of Dendritic Cell Maturation and Function Is Independent of Heme Oxygenase 1 but Requires the Activation of STAT3

Cited by 36 publications

References 51 publications

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1

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

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