A Review on Heme Oxygenase1 Induction Is It a Necessary Evil

Abstract

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are non completely understood. IVIG interacts with numerous components of the allowed system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies accept reported that heme oxygenase-ane (HO-1) pathway plays an of import role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, nosotros aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we study that IVIG exerts anti-inflammatory furnishings on innate cells as shown by the inhibitory effects on IL-vi and nitric oxide product and confers protection in experimental autoimmune encephalomyelitis (EAE) model. Yet, these effects were non associated with an consecration of HO-ane either in innate cells such every bit monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. As well, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus bespeak that IVIG exerts anti-inflammatory effects contained of HO-1 pathway.

Introduction

Initially used as replacement therapy in immune deficiencies, IVIG is also widely used for the treatment of a number of autoimmune and systemic inflammatory diseases^1,2,3,4,5. Despite its therapeutic utilize for more iii decades, the precise mechanism by which IVIG exerts its beneficial effect is not fully understood. Exploration of mechanisms of IVIG is useful to define the dosage, to identify an appropriate window and duration of treatment and to delineate biomarkers of therapeutic response. IVIG interacts with numerous components of the allowed system including dendritic cells (DCs), macrophages, T and B cells and modulate their functions^{vi,7,viii,ix,10,11,12,13,fourteen,15,16,17,eighteen,nineteen,twenty,21}. These mechanisms of IVIG likewise reflect the functions of circulating IgG in the maintenance of allowed homeostasis.

Recent studies in various experimental models such as sepsis, cardiovascular pathologies, experimental autoimmune encephalomyelitis (EAE) and transplantation and infection models such as Mycobacterium tuberculosis have highlighted the biological significance of heme oxygenase-one (HO-1) enzymatic pathway and the reactive products of this pathway in regulating the inflammation and in the adaptation of the pathogens to the host microenvironment^{22,23,24,25,26,27,28}. HO-1 catalyzes the degradation of heme, resulting in the liberation of equimolar amounts of iron, carbon monoxide (CO) and biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Built defects in HO-ane expression in mice and human are associated with systemic inflammation²⁹. HO-one inhibits ovalbumin-induced airway inflammation by enhancing the biological activeness of regulatory T cells (Tregs) in an IL-ten-dependent manner³⁰. Nevertheless, development, maintenance and the functions of Tregs under physiological conditions are not dependent on the activity of HO-i³¹.

CO and biliverdin take stiff anti-inflammatory, anti-proliferative, anti-apoptotic and antioxidant activities and exert their effects on many prison cell types, including cells of the allowed system³². CO suppresses the pro-inflammatory response and promotes the anti-inflammatory programs of macrophages, DCs and monocytes^33,34. Thus, either overexpression of HO-one in innate cells or exposure to CO leads to inhibition of pro-inflammatory cytokines and enhancement of IL-10. CO also inhibits the lipopolysaccharide (LPS)-mediated maturation of DCs^35,36.

Thus, in view of the mutual anti-inflammatory part exerted by both HO-1 and IVIG, we investigated if mechanisms of action of IVIG both in vitro and in vivo implicate HO-one pathway.

Results

Anti-inflammatory effects of IVIG on human being monocytes are not associated with induction of HO-ane

It is known that IVIG exerts anti-inflammatory effects on innate cells such as monocytes, DCs and macrophages leading to suppression of inflammatory cytokines^8,37,38,39. By analysing the production of IL-6, we first confirmed the anti-inflammatory activeness of IVIG. Unstimulated monocytes produced insignificant amount of IL-half dozen. However, upon stimulation with LPS, a TLR4-agonist, monocytes produced big amounts of IL-six. Importantly, IVIG significantly reduced the product of IL-6, thus validating the anti-inflammatory furnishings of IVIG (Fig. 1a). The inhibition still was not dependant on the dose of IVIG.

We and then examined the issue of IVIG on the expression of HO-one. Untreated monocytes expressed marginal amount of HO-1 and was not modified by IVIG. Even nether inflammatory weather, IVIG failed to induce the expression of HO-1 (Fig. 1b) in all tested concentrations. The lack of expression of HO-1 in IVIG-treated monocytes was not due to technical errors or non-functioning of HO-1-detecting antibodies as treatment of monocytes with cobalt protoporphyrin 9 (CoPP), an inductor of HO-1, strongly induced HO-1. These results thus suggest that anti-inflammatory effects of IVIG on monocytes are contained of HO-1 pathway.

Inability of IVIG to induce HO-1 in dendritic cells and macrophages

Nosotros investigated the consequence of IVIG on the expression of HO-one in other innate cells. Consistent with the results obtained with monocytes, IVIG did non induce HO-1 both in monocyte-derived homo DCs as well as RAW264.7 macrophage cell line (Fig. 2a,b). CoPP, the positive control, induced HO-1 in both the cell types. These results thus indicate that disability of IVIG to induce HO-i is not restricted to particular innate cell.

Inhibition of endogenous HO-1 is not coupled with reduced operation of IVIG

As innate cells limited basal level of HO-1 (Fig. 1b, 2b), nosotros wondered whether inhibition of this endogenous HO-i is associated with reduced anti-inflammatory action of IVIG. Peritoneal macrophages from C57BL/6J mice and RAW264.7 cells were treated with IVIG for 24 hours and followed past stimulation with LPS. The activation of macrophages by LPS leads to oxidation of L-arginine via nitric oxide synthase and produce nitric oxide (NO). Equally shown in Fig. 3a,b, IVIG significantly inhibited LPS-induced NO production. However, treatment of cells with tin-mesoporphyrin (SnMP) to suppress enzyme activeness of the endogenous HO-1 did not inhibit anti-inflammatory effects of IVIG on NO production (Fig. 3a,b).

The protective effect of IVIG in experimental autoimmune encephalomyelitis is contained of induction of HO-1 in vivo

In order to validate the not-involvement of HO-1 pathway in IVIG-mediated anti-inflammatory effects in vivo, we resorted to EAE model. EAE was induced in C57BL/6J mice using MOG_35–55. Confirming the previous reports, treatment of mice with IVIG significantly delayed the onset of EAE and the severity of the disease (Fig. 4a)^xl,41,42. However, consistent with in vitro results, this protection was not associated with an induction of HO-1 irrespective of the organs examined (liver and kidney) (Fig. 4b). Western blot assay of lungs and spleen besides showed same results. Naive mice injected with CoPP (xx mg/kg) were used every bit positive control for the expression of HO-1. In fact, expression of HO-1 was confirmed in the liver and kidneys of these mice 24 hours following CoPP injection (Fig. 4b).

Word

It was suggested that HO-1 functions as a "therapeutic funnel"³². Several reports in experimental models have recently demonstrated that HO-1 pathway and its products could exist used for the prevention or handling of immune-mediated disorders. These protective furnishings are mediated past multiple functions of HO-one that include immunosuppression, anti-inflammatory, anti-apoptosis and anti-oxidant effects. The anti-inflammatory mechanisms of HO-ane are mainly via modulation of activation of allowed cells including antigen presenting cells and lymphocytes³². In fact, IVIG has been demonstrated to modulate the functions of both innate cells and T cells. Thus, IVIG was reported to suppress the activation of DCs, macrophages and monocytes and secretion of inflammatory cytokines while enhancing anti-inflammatory mediators like IL-10 and IL-1ra. In addition, IVIG also inhibits APC-mediated effector T prison cell activation, proliferation. Recent reports farther demonstrate that IVIG inhibits Th1 and Th17 subsets, which are pathogenic in diverse autoimmune and inflammatory diseases and reciprocally expands Tregs^{40,41,42,43,44,45,46,47,48}. Chiefly, HO-ane appears to be required for the action of several therapeutic molecules. For instance, rapamycin appears not to exert its anti-proliferative effects on smooth musculus cells unless HO-1 is nowadays⁴⁹. All these unlike lines of evidence underscore the importance of dissection of HO-one pathway in the anti-inflammatory effects of IVIG.

Previous reports have shown that innate cells express HO-i in steady state and inhibit price-like receptor-mediated (such as LPS) activation and secretion of pro-inflammatory cytokines^35,36,50. Although, the expression of HO-1 in monocytes, DC and RAW264.vii was non prominent, we could detect basal expression of poly peptide past western blot. Nevertheless, IVIG did not modulate the basal expression of HO-ane. Thus, suppression of LPS-mediated IL-6 and NO production by IVIG were independent of HO-1 pathway. It could be argued that IVIG-mediated suppression of IL-6 and NO might be due to passive neutralization of LPS by antibodies as we pre-treated the innate cells with IVIG before stimulation with LPS. However, as analyzed past the expression of CD80 and CD86, IVIG-mediated anti-inflammatory furnishings was well-preserved in the monocytes even if cells were stimulated with LPS followed by treatment with IVIG (Supplementary Fig. S1), thus ruling out passive neutralization of LPS every bit a mechanism of anti-inflammatory effect of IVIG. As activation stimuli such as LPS were reported to inhibit the expression of HO-ane³⁵, nosotros opted for examining if IVIG-preconditioning results in HO-1 expression in innate cells, which in turn inhibits LPS-mediated activation of cells. Our information even so clearly demonstrates that IVIG or otherwise, normal circulating antibodies lack the chapters to induce HO-1 and even upon inhibition of endogenous HO-one, IVIG-mediated anti-inflammatory furnishings were not altered.

Tregs play an important role in the prevention of autoimmune and inflammatory responses⁵¹. Initial reports take indicated that HO-1 in Tregs is critical for their allowed suppression functions⁵². However, subsequent reports accept contradicted this data and showed that HO-one expression in Tregs is not key for immunoregulatory functions of these cells both in human and mice^31,53. Every bit stimuli from DCs are crucial in Treg expansion, subsequent report showed that HO-1 expression in DCs mediated suppressive functions of Tregs⁵⁴. Despite induction of DC-mediated Treg expansion by IVIG every bit reported recently by united states of america and others, we could not observe consecration of HO-1 in DCs by IVIG suggesting that IVIG targets different pathways for the expansion of Tregs. In fact, several lines of bear witness suggest that IVIG could expand Tregs via numerous mechanisms, which might deed either contained or inter-linked^{18,19,40,42,48}. The modulation of DC functions upon recognition of IVIG via DC-SIGN or DICER constitutes a major event^xl,48. This interaction leads to expression of COX-2-dependent PGE2 production in DCs, which in turn expands Tregs. The role of PGE2 in IVIG-mediated Treg expansion was documented both in vivo in animal models and in autoimmune patients treated with IVIG^40,45.

Experimental models have shown that HO-1 pathway inhibits pathogenic T jail cell responses. EAE has been used equally an experimental model for multiple sclerosis and that induction of HO-ane pathway suppress neuro-inflammation in EAE²³. Induction of HO-one also suppressed IFN-γ and TNF-α responses of CNS-infiltrating T cells. Suppression of Th1 responses by HO-1 was likewise reported in type ane diabetes model in NOD mice²⁵. Although modulation of Th17 responses by HO-i in EAE was not analyzed in the previous report, it is probable that HO-1 suppresses Th17 responses equally anti-inflammatory functions of HO-1 in non-eosinophilic asthma were associated with inhibition of Th17 responses⁵⁵.

Several therapeutic strategies including injection of tolerogenic cells, recombinant proteins, monoclonal antibodies to inflammatory cytokines, pharmacological agents and oral tolerance accept been explored in EAE^56,57. Notwithstanding, long-term safety issues and specially in pregnant and lactating women are of major concern with currently used therapies for MS⁵⁸. Promising clinical results in relapsing-remitting multiple sclerosis prompted dissection of cellular and molecular mechanisms of action of IVIG in EAE⁵⁸. We have recently reported that IVIG inhibits both Th1 and Th17 responses in EAE model⁴¹ and like to HO-1 induction model of Chora et al.²³, significantly inhibited CNS infiltration of T cells. Confirming the in vitro results, the protection rendered by IVIG in EAE was not associated with HO-1 consecration. Information technology was however not surprising given that endogenous expression of HO-1 had no outcome on EAE and daily injection of CoPP was required to induce HO-1 in mice and to protect from EAE²³. Current data testify that without activating HO-i, therapeutic benefits could exist obtained in EAE. Thus, our results exemplify the multi-faceted mechanisms of IVIG to exert anti-inflammatory effects independent of HO-1 pathway. These results could be further consolidated past using HO-ane-deficient mice. Notwithstanding, data from such mice would be hard to interpret due to circuitous interactions of the HO-1 pathway products with diverse immune and non-immune cells.

IVIG products are not uniform and display variations with respect to conception, stabilizing agents and source of plasma of salubrious donors. Although these variations could influence the effect of therapy of main immunodeficiency patients, all IVIG products appear to accept similar therapeutic benefits in autoimmune patients. Of annotation, when different IVIG preparations were examined for their event on DC activation, endothelial functions and Th17 differentiation and expansion, all tested IVIG preparations exerted similar effects^37,59. In this written report, nosotros found that lack of consecration of HO-1 past IVIG is not restricted to particular innate cell or IVIG preparation. In addition to Gamunex®, other three IVIG preparations (Sandoglobulin®, Tegeline® and Gammagard®) were also inefficient to induce HO-1. Thus, our data indicate that disability of IVIG to induce HO-1 is a universal phenomenon irrespective of preparations.

Methods

Homo Jail cell culture

Buffy coats from the healthy donors were purchased from Centre Necker-Cabanel, Etablissement Français du Sang (EFS), Paris, France. Ethical committee permission was obtained for the use of buffy bags of healthy donors (Institut National de la Santé et de la Recherche-EFS ethical committee permission N°12/EFS/079) and experiments were performed in accordance with the approved guidelines of INSERM. Peripheral blood mononuclear cells (PBMCs) were purified from the buffy coats by density slope centrifugation using Ficoll-paque PREMIUM (GE healthcare, France). CD14⁺ monocytes were isolated from PBMCs by positive pick with CD14 microbeads (Miltenyi Biotec, France). They were cultured for 6 days in RPMI-1640 medium plus 10% fetal calf serum containing GM-CSF (1000 IU/meg cells) and IL-4 (500 IU/million cells) to obtain monocyte-derived DCs^sixty.

Murine macrophages

All animal studies were canonical and performed according to the guidelines of Charles Darwin upstanding committee for beast experimentation (Université Pierre et Marie Curie Paris) at the pathogen-free animate being facility of Centre de Researche des Cordeliers, Paris. Murine peritoneal macrophages were extracted from C57BL/6J mice (purchased from Janvier Laboratories, France) by intraperitoneal lavage and cultured in Dubelcco's Modified Eagle's Medium supplemented with 1% penicillin, 1% streptomycin, 5% amino acids and 5% fetal bovine serum.

Murine RAW264.seven macrophages were maintained in Dubelcco's Modified Eagle's Medium supplemented with 1% penicillin, 1% streptomycin, 5% amino acids and 5% fetal bovine serum.

All cells were maintained at 37 °C in humidified air containing 5% CO_ii.

Preparations of IVIG

Gamunex® (Grifols Bioscience, USA) was used throughout the report. In addition, Gammagard®, Sandoglobulin® and Tegeline® were also used for in vitro experiments. They were dialysed against a big volume of PBS followed by RPMI-1640 medium at four °C for xviii hours to remove the stabilizing agents. IVIG was used at concentrations of five, 10 or xv mg/ml/0.5 million cells.

Animals and EAE

All fauna studies were approved and performed co-ordinate to the guidelines of Charles Darwin ethical committee for animal experimentation (Université Pierre et Marie Curie Paris) at the pathogen-free animal facility of Centre de Researche des Cordeliers, Paris.

Ten-week former C57BL/6J mice (purchased from Janvier Laboratories, France) were injected intraperitoneal with CoPP 20 mg/kg. Subsequently 24 hours, liver and kidney were recovered and snap-frozen for western-blot analysis to check the HO-ane expression.

To induce EAE, C57BL/6J mice (ten/group) were immunized with 200 μg MOG_35–55 peptide emulsified in complete Freund's adjuvant (one:1 by volume containing 800 μg of nonviable desiccated Mycobacterium tuberculosis H37Rv. In addition, 300 ng of pertussis toxin was given intravenously on the aforementioned day and two days afterward. Clinical signs of EAE were assessed daily based on the following scoring system: 0, no signs; 1, tail paresis; 2, hind limb paresis; 3, hind limb paralysis; 4, tetraplegia; and 5, moribund. From the day of the immunization until the tiptop of the disease (day 19), mice received daily intraperitoneal injections of sixteen mg (0.8 g/kg) IVIG (Gamunex®). The control groups received equal volumes of 0.two M glycine, the excipient of Gamunex®).

Detection of HO-1 by Western blot

Human monocytes, DCs and RAW264.vii macrophages (0.5 million cells per ml) were treated with dissimilar IVIG preparations and with CoPP 25 μM, the activator of HO-1. Later on 24 hours, supernatants were removed and cells were lysed with a lysis buffer (20 mM dithiothreitol, 6% SDS, 0.25 Thousand Tris, 10% glycerol and 10 mM Na Fluoride, pH = 6.8). In another prepare of experiments, following 24 hours handling of monocytes with IVIG, LPS (10 ng/ml; Sigma-Aldrich, France) was added to the cells to stimulate the monocytes and to induce inflammatory cytokines. After 24 hours, supernatants were removed and cells were lysed.

Liver and kidneys from EAE mice at the elevation of the disease (twenty-four hour period xix following induction of EAE) or from the mice injected with CoPP were lysed with the lysis buffer.

Proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions and transferred to polyvinylidene fluoride membrane. HO-1 was detected using an anti-HO-1 rat monoclonal IgG (R&D Systems, French republic), a horseradish peroxidase-conjugated rabbit anti-rat IgG and the enhanced chemiluminescence kit. β-actin was detected with a mouse anti-β-actin antibody (Sigma-Aldrich).

Phenotype analysis of monocytes treated with IVIG

Peripheral claret monocytes from the healthy donors were stimulated with LPS for 30 min. They were then exposed to IVIG for 48 hours. The expression of CD80 and CD86 was analyzed by flow cytometry using PE-conjugated MAbs to CD80 and FITC-conjugated MAbs to CD86 (both from BD Biosciencies).

Cytokine analysis

IL-vi in the cell-free culture supernatants was quantified by ELISA (Prepare-SET-Become, eBioscience, France). The detection limit was 2 pg/ml.

Measurement of NO production

Peritoneal macrophages from C57Bl/6J mice and RAW264.7 cells were treated with IVIG (x mg/ml) for 24 hours. They were so exposed to either LPS lone or LPS and SnMP (25 μM; Frontier Scientific, USA) for additional 24 hours. Production of NO was evaluated by Griess method.

Statistical analysis

Two-manner analysis of variance (ANOVA) with Bonferroni'southward post-test was used to analyze daily clinical score. One-way ANOVA was used to decide the statistical significance of the in vitro data. P value of less than 0.05 was considered significant.

Additional Information

How to cite this article: Galeotti, C. et al. Heme oxygenase-one is dispensable for the anti-inflammatory activity of intravenous immunoglobulin. Sci. Rep. half dozen, 19592; doi: 10.1038/srep19592 (2016).

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Acknowledgements

This study was supported past Institut National de la Santé et de la Recherche Médicale (INSERM), Heart National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie, Université Paris Descartes, the Indo-French Center for Promotion of Advanced Research (CEFIPRA, grant 4803-1), eSPIN (European Scientific Progress – Immunoglobulins in Neurology) award 2009 by Grifols. C.One thousand. is a recipient of fellowship from La Fondation pour la Recherche Médicale, France. V.One thousand.Southward is a recipient of fellowship from INSERM under International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France - Indian council of Medical Research, India) scheme.

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Affiliations

Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France

Caroline Galeotti, Pushpa Hegde, Mrinmoy Das, Emmanuel Stephen-Victor, Fernando Canale, Marcos Muñoz, Varun Thou. Sharma, Jordan D. Dimitrov, Srini V. Kaveri & Jagadeesh Bayry
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France

Caroline Galeotti, Mrinmoy Das, Emmanuel Stephen-Victor, Jordan D. Dimitrov, Srini V. Kaveri & Jagadeesh Bayry
Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France

Caroline Galeotti, Pushpa Hegde, Mrinmoy Das, Emmanuel Stephen-Victor, Fernando Canale, Marcos Muñoz, Varun K. Sharma, Jordan D. Dimitrov, Srini V. Kaveri & Jagadeesh Bayry
Department of Pediatric Rheumatology, National Referral Centre of Auto-inflammatory Diseases, CHU de Bicêtre, F-94270, le Kremlin Bicêtre, France

Caroline Galeotti
Université Paris Descartes, Sorbonne Paris Cité, UMR Due south 1138, Paris, F-75006, France

Hashemite kingdom of jordan D. Dimitrov, Srini V. Kaveri & Jagadeesh Bayry
International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France - Indian council of Medical Inquiry, India), National Institute of Immunohaematology, Mumbai, 400012, India

Srini V. Kaveri & Jagadeesh Bayry

Contributions

C.G., P.H., Chiliad.D., E.S.-V., F.C., M.M. and 5.K.South. performed the experiments, C.G., P.H., J.D.D., S.5.K. and J.B. analyzed the data, C.G. and J.B. wrote the paper and all authors reviewed and approved the manuscript.

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Galeotti, C., Hegde, P., Das, K. et al. Heme oxygenase-ane is dispensable for the anti-inflammatory activity of intravenous immunoglobulin. Sci Rep 6, 19592 (2016). https://doi.org/ten.1038/srep19592

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Received: 16 July 2015
Accepted: 30 Nov 2015
Published: 22 January 2016
DOI : https://doi.org/10.1038/srep19592

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Source: https://www.nature.com/articles/srep19592