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Heme Oxygenase-1-Expressing Dendritic Cells Promote Foxp3+ Regulatory T Cell Differentiation and Induce Less Severe Airway Inflammation in Murine Models.

ABSTRACT: Dendritic cells (DCs) are critical for instructing immune responses toward inflammatory or anti-inflammatory status. Heme oxygenase-1 (HO-1) is known for its cytoprotective effect against oxidative stress and inflammation, suggesting its immune regulatory role in allergic lung inflammation. HO-1 has been implicated in affecting DC maturation; however, its role in DC-mediated T-cell differentiation is unclear. In this study, we demonstrated that HO-1-expressing bone marrow-derived dendritic cells (BM-DCs) displayed tolerogenic phenotypes, including their resistance to lipopolysaccharide (LPS)-induced maturation, high level expression of IL-10, and low T-cell stimulatory activity. In addition, HO-1-expressing DCs were able to induce antigen-specific Foxp3+ regulatory T cells (Treg) differentiation in vitro and in vivo. Also, HO-1-expressing DCs modulated the severity of lung inflammatory responses in two murine models of airway inflammation. This study provided evidence supporting the role of HO-1-expressing DCs in tolerance induction and as a potential therapeutic target for allergic asthma as well as other inflammatory diseases.

SUBMITTER: Wong TH

PROVIDER: S-EPMC5199094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Heme oxygenase-1 expression in murine dendritic cell subpopulations: effect on CD8+ dendritic cell differentiation in vivo.

Project description:Heme oxygenase-1 (HO-1) is a microsomal enzyme with antioxidant, antiapoptotic, and immunoregulatory functions. We studied the expression of HO-1 by bone marrow-derived dendritic cells (BMDCs) and splenic DC subpopulations under quiescent conditions or following lipopolysaccharide (LPS) stimulation. The kinetics of HO-1 expression by BMDCs depended on the conditions under which they were propagated. Expression of HO-1 in mouse BMDCs in 100 U/ml GM-CSF peaked at 16 hours after LPS treatment and maintained expression for at least 48 hours. But cultures in 800 U/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) showed peak expression by 16 hours that disappeared by 48 hours after LPS stimulation, similar to BMDCs cultured in both 100 U/ml GM-CSF and IL-4 (10 ng/ml). By flow cytometry, a large proportion of CD8(+) splenic DCs strongly expressed HO-1, and this population significantly increased following LPS administration in vivo. In HO-1(-/-) mice, the proportion of splenic CD8(+) DCs was significantly decreased in comparison with HO-1(+/+) mice. In addition, a unique subpopulation of MHC II(-)CD11b(+)CD11c(+) cells was prominent in HO-1(-/-) spleens. Injection of GFP-labeled HO-1(+/+) splenic DC precursors into HO-1(+/+) mice resulted in the generation of GFP(+)CD8(+) DCs in the spleen after 5 days, but GFP(+) CD8(+) DCs failed to appear in HO-1(-/-) spleens. Conversely, GFP(+)HO-1(-/-) splenic cells also generated GFP(+)CD8(+) DCs in HO-1(+/+) mice. These results show that HO-1 is involved in splenic DC differentiation, and/or the homing of CD8(+) splenic DC precursors appears to be dependent on HO-1 expression by the host.

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Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

Project description:Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

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Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension.

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| S-EPMC3422740 | biostudies-literature

CD8???? and CD8???? plasmacytoid dendritic cells induce Foxp3? regulatory T cells and prevent the induction of airway hyper-reactivity.

Project description:Dendritic cells (DCs) control the balance between protection against pathogens and tolerance to innocuous or self-antigens. Here, we demonstrate for the first time that mouse plasmacytoid DCs (pDCs) can be segregated into three distinct populations, exhibiting phenotypic and functional differences, according to their surface expression of CD8? or CD8? as CD8????, CD8????, or CD8????. In a mouse model of lung inflammation, adoptive transfer of CD8???? or CD8???? pDCs prevents the development of airway hyper-reactivity. The tolerogenic features of these subsets are associated with increased production of retinoic acid, which leads to the enhanced induction of Foxp3? regulatory T cells compared with CD8???? pDCs. Our data thus identify subsets of pDCs with potent tolerogenic functions that may contribute to the maintenance of tolerance in mucosal sites such as the lungs.

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Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance.

Project description:Dendritic cell (DC)-T cell interactions that underlie inducible/adaptive regulatory T cell generation and airway tolerance are not well understood. In this study, we show that mice lacking CD11c(hi) lung DCs, but containing plasmacytoid DCs (pDCs), fail tolerization with inhaled Ag and cannot support Foxp3 induction in vivo in naive CD4(+) T cells. CD103(+) DCs from tolerized mice efficiently induced Foxp3 in cocultured naive CD4(+) T cells but pDCs and lung macrophages failed to do so. CD103(+) DCs, but not pDCs or lung macrophages, upregulated the expression of retinaldehyde dehydrogenase 2 (aldh1a2), which is key for the production of retinoic acid, a cofactor for TGF-? for Foxp3 induction. Batf3(-/-) mice, selectively lacking CD103(+) DCs, failed tolerization by inhaled Ag. Collectively, our data show that pulmonary tolerance is dependent on CD103(+) DCs, correlating with their ability to upregulate aldh1a2, which can promote Foxp3 expression in T cells.

| S-EPMC3694746 | biostudies-literature

Orthodontic Forces Induce the Cytoprotective Enzyme Heme Oxygenase-1 in Rats.

Project description:Orthodontic forces disturb the microenvironment of the periodontal ligament (PDL), and induce craniofacial bone remodeling which is necessary for tooth movement. Unfortunately, orthodontic tooth movement is often hampered by ischemic injury and cell death within the PDL (hyalinization) and root resorption. Large inter-individual differences in hyalinization and root resorption have been observed, and may be explained by differential protection against hyalinization. Heme oxygenase-1 (HO-1) forms an important protective mechanism by breaking down heme into the strong anti-oxidants biliverdin/bilirubin and the signaling molecule carbon monoxide. These versatile HO-1 products protect against ischemic and inflammatory injury. We postulate that orthodontic forces induce HO-1 expression in the PDL during experimental tooth movement. Twenty-five 6-week-old male Wistar rats were used in this study. The upper three molars at one side were moved mesially using a Nickel-Titanium coil spring, providing a continuous orthodontic force of 10 cN. The contralateral side served as control. After 6, 12, 72, 96, and 120 h groups of rats were killed. On parasagittal sections immunohistochemical staining was performed for analysis of HO-1 expression and quantification of osteoclasts. Orthodontic force induced a significant time-dependent HO-1 expression in mononuclear cells within the PDL at both the apposition- and resorption side. Shortly after placement of the orthodontic appliance HO-1 expression was highly induced in PDL cells but dropped to control levels within 72 h. Some osteoclasts were also HO-1 positive but this induction was shown to be independent of time- and mechanical stress. It is tempting to speculate that differential induction of tissue protecting- and osteoclast activating genes in the PDL determine the level of bone resorption and hyalinization and, subsequently, "fast" and "slow" tooth movers during orthodontic treatment.

| S-EPMC4949267 | biostudies-literature

Polyclonal CD4+Foxp3+ Treg cells induce TGF?-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome.

Project description:Interplay between Foxp3(+) regulatory T cells (Treg) and dendritic cells (DCs) maintains immunologic tolerance, but the effects of each cell on the other are not well understood. We report that polyclonal CD4(+)Foxp3(+) Treg cells induced ex vivo with transforming growth factor beta (TGF?) (iTreg) suppress a lupus-like chronic graft-versus-host disease by preventing the expansion of immunogenic DCs and inducing protective DCs that generate additional recipient CD4(+)Foxp3(+) cells. The protective effects of the transferred iTreg cells required both interleukin (IL)-10 and TGF?, but the tolerogenic effects of the iTreg on DCs, and the immunosuppressive effects of these DCs were exclusively TGF?-dependent. The iTreg were unable to tolerize Tgfbr2-deficient DCs. These results support the essential role of DCs in 'infectious tolerance' and emphasize the central role of TGF? in protective iTreg/DC interactions in vivo.

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Macrophages expressing heme oxygenase-1 improve renal function in ischemia/reperfusion injury.

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Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3<sup>+</sup> regulatory T cells in murine colon cancer.

Project description:The colorectal tumor microenvironment contains a diverse population of myeloid cells that are recruited and converted to immunosuppressive cells, thus facilitating tumor escape from immunoediting. We have identified a genetically and functionally distinct subset of dynamic bone marrow myeloid cells that are characterized by histidine decarboxylase (HDC) expression. Lineage tracing in Hdc-CreERT2;R26-LSL-tdTomato mice revealed that in homeostasis, there is a strong bias by HDC+ myeloid cells toward the CD11b+Ly6Ghi granulocytic lineage, which was accelerated during azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colonic carcinogenesis. More importantly, HDC+ myeloid cells strongly promoted colonic tumorigenesis, and colon tumor progression was profoundly suppressed by diphtheria toxin A (DTA)-mediated depletion of HDC+ granulocytic myeloid cells. In addition, tumor infiltration by Foxp3+ regulatory T cells (Tregs) was markedly impaired following HDC+ myeloid cell depletion. We identified an HDC+ myeloid-derived Cxcl13/Cxcr5 axis that mediated Foxp3 expression and Treg proliferation. Ablation of HDC+ myeloid cells or disruption of the Cxcl13/Cxcr5 axis by gene knockdown impaired the production and recruitment of Tregs. Cxcl13 induction of Foxp3 expression in Tregs during tumorigenesis was associated with Stat3 phosphorylation. Overall, HDC+ granulocytic myeloid cells affect CD8+ T cells directly and indirectly through the modulation of Tregs and thus appear to play key roles in suppressing tumoricidal immunity.

| S-EPMC5384347 | biostudies-literature

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| S-EPMC4007628 | biostudies-literature

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