Heme Oxygenase-1 Dysregulates Macrophage Polarization and the Immune Response to <i>Helicobacter pylori</i>

Gobert, Alain P.; Verriere, Thomas G.; Asim, Mohammad; Barry, Daniel P.; Piazuelo, M. Blanca; Sablet, Thibaut de; Delgado, Alberto; Bravo, Luis Eduardo; Correa, Pelayo; Peek, Richard M.; Chaturvedi, Rupesh; Wilson, Keith T.

doi:10.4049/jimmunol.1401075

Cited by 69 publications

(81 citation statements)

References 58 publications

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“…The increased frequencies and enhanced suppressive activity of GARP + CD4 + CD25 + Tregs could effectively inhibit the hyperproliferation of Th1 cells to maintain immune homeostasis by direct cell-cell contact and the expression of anti-inflammatory cytokine TGF-β1. HO-1 has been shown to suppress Th17 cell-mediated immune response in some animal models [40,41]. Now, we further confirmed that HO-1 inhibited the Th17-dominant response in patients with ACS.…”

Section: Discussionsupporting

confidence: 75%

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Liu

Zhao

Zhong

et al. 2015

Cell Physiol Biochem

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Background: Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4⁺CD25⁺regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) ⁺ CD4⁺ CD25⁺ activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP⁺ CD4⁺ CD25⁺Tregs in patients with ACS and thus regulate immune imbalance. Methods: T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) ⁺CD4⁺ T cells and the expression of Foxp3 and GARP by CD4⁺CD25⁺T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Results: Patients with ACS exhibited an impaired number and suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP⁺ CD4⁺ CD25⁺Tregs and resulted in increased expression of LAP and GARP by activated T cells. Conclusions: The reduced number and impaired suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP⁺ CD4⁺ CD25⁺Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells.

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Section: Discussionsupporting

confidence: 75%

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Liu

Zhao

Zhong

et al. 2015

Cell Physiol Biochem

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“…Male mice were selected because previous studies have demonstrated that female mice are protected from gastric damage during H. pylori infection (60). Sample sizes were based on previous studies (14,25,42,61). No other selection criteria were used in these studies.…”

Section: Methodsmentioning

confidence: 99%

Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications

Hardbower

Asim

Luis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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163

179

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Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms. macrophage polarization | polyamines | histone modifications | ornithine decarboxylase | Helicobacter pylori

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“…Gobert and colleagues demonstrated, in both mice and men, that the Cag ? H. pylori strain induces gastric macrophages to express hemeoxygenase 1 (HO-1), which restrains transcription of pro-inflammatory M1 genes and upregulates selected regulatory genes (i.e., IL-10) [116]. Additional studies showed either in vitro or in vivo (i.e., gastric mucosa of mice and humans) that H. pylori induces macrophages to express the M2 markers arginase II (Arg2) [117][118][119], Ornithine decarboxylase (ODC) [120,121], and Spermine oxidase (SMO) [122,123].…”

Section: Helicobacter Pylori Infectionmentioning

confidence: 99%

Macrophage polarization in pathology

Sica

Erreni

Allavena

et al. 2015

Cell. Mol. Life Sci.

528

422

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Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.

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Heme Oxygenase-1 Dysregulates Macrophage Polarization and the Immune Response to Helicobacter pylori

Cited by 69 publications

References 58 publications

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications

Macrophage polarization in pathology

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