scholarly journals Characterizing the distributions of IDO-1 expressing macrophages/microglia in human and murine brains and evaluating the immunological and physiological roles of IDO-1 in RAW264.7/BV-2 cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258204
Author(s):  
Rong Ji ◽  
Lixiang Ma ◽  
Xinyu Chen ◽  
Renqiang Sun ◽  
Li Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Human Brain ◽  
Human Blood ◽  
Blood Monocytes ◽  
Phagocytic Capacity ◽  
Fluid Uptake ◽  
Mouse Macrophages ◽  
Human And Mouse ◽  
Nlrp3 Expression

Indoleamine 2,3-dioxygenase 1 (IDO-1) is an immunosuppressive enzyme expressed in the placenta, neoplastic cells, and macrophages to reject T cells by converting tryptophan into kynurenine. However, the role of IDO-1 in brain immunity, especially in the meninges, is unclear. We aim to elucidate the distribution pattern of IDO-1+ macrophages/microglia in the human brain tissues, human glioblastoma, APP/PS1 mouse brains, and quinolinic acid model brains and explore the physiological and immunological roles of IDO-1+ macrophages/microglia. Here, we find that both human and mouse macrophages/microglia of the perivascular and subarachnoid space and in glioblastoma (GBM) expressed IDO-1 but not macrophages/microglia of parenchyma. Using IDO-1 inhibitors including 1-MT and INCB24360, we observed that inhibiting IDO-1 reduced the cellular size and filopodia growth, fluid uptake, and the macropinocytic and phagocytic abilities of human blood monocytes and RAW264.7/BV-2 cells. Inhibiting IDO-1 with 1-MT or INCB24360 increased IL-1β secretion and suppressed NLRP3 expression in RAW264.7/BV-2 cells. Our data collectively show that IDO-1 expression in perivascular and meninges macrophages/microglia increases cellular phagocytic capacity and might suppress overactivation of inflammatory reaction.

scholarly journals Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10

2019 ◽  
Vol 216 (2) ◽  
pp. 337-349 ◽  
Author(s):  
Peng Xiao ◽  
Huilun Zhang ◽  
Yu Zhang ◽  
Mingzhu Zheng ◽  
Rongbei Liu ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Blood Monocytes ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Mouse Macrophages ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Further Development

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.

scholarly journals Autophagy is required for CSF-1–induced macrophagic differentiation and acquisition of phagocytic functions

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4527-4531 ◽  
Author(s):  
Arnaud Jacquel ◽  
Sandrine Obba ◽  
Laurent Boyer ◽  
Maeva Dufies ◽  
Guillaume Robert ◽  
...  
Keyword(s):  
Human Blood ◽  
Essential Role ◽  
Ex Vivo ◽  
Colony Stimulating Factor ◽  
Blood Monocytes ◽  
Monocyte Differentiation ◽  
Pharmacologic Inhibitors ◽  
Pleiotropic Functions ◽  
Stimulating Factor

Abstract Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7−/− mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1–driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions.

scholarly journals INCB24360 Suppresses M1-like Macrophage Formation and NLRP3 Expression Whereas Increases IL-1β Secretion in RAW264.7 and BV-2

2020 ◽  
Author(s):  
Rong Ji ◽  
Lixiang Ma ◽  
Xinyu Chen ◽  
Renqiang Sun ◽  
Li Zhang ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Phagocytic Capacity ◽  
Tissue Macrophage ◽  
Phagocytic Ability ◽  
Fluid Uptake ◽  
Cast Doubt ◽  
Ifn Γ ◽  
Ido Inhibitors ◽  
Nlrp3 Expression

Abstract Background: Macrophages switch between different functional phenotypes under the different physiological or path-physiological stimuli in tissue. Macrophage functional phenotype heavily affects disease progression, including inflammation, injury, neurodegenerative disease, and cancers. IDO-1, a druggable target, is an immunosuppressive enzyme expressed in tissue macrophages and induced by Interferon-γ (IFN-γ). How IDO-1 inhibitors affect the functional switches of macrophage are unknown. Methods: IFN-γ were used to increase IDO-1 expression and 1-Methyl-D-tryptophan (1-MT) and INCB24360 (Epacadostat) were used to inhibit IDO-1 activity in RAW264.7 and BV-2. Western blotting, immunostaining and ELISA were used to evaluate protein expressions or secretion. RT-PCR were used to assess to transcription. TMR-Dextran and Latex beads were used to test endocytic, macropinocytic and phagocytic ability of macrophage and Fiji image and IMARIS were used to analyze images.Results: Our results showed that INCB24360 preferentially suppresses the cellular size and filopodia growth and reduces fluid uptake, macropinocytosis, and phagocytic ability of IFN-γ induced or non-induced RAW264.7 and BV-2 in vitro. 1-MT and INCB24360 suppress IFN-γ induced or endogenous NLRP3 expression levels but not caspase-1 in RAW264.7 and BV-2. NLRP3 reduction induced by 1-MT and INCB24360 parallel with the decrease of NLRP3 gene transcription and an increase of IL-1β secretion. Conclusions: Our data collectively showed that inhibiting IDO-1 with its inhibitors, especially INCB24360, preferentially suppresses cellular size and filopodia growth, NLRP3 expression, the endocytic, macropinocytic, and phagocytic capacity whereas increases IL-1β secretion in macrophage. Our findings do not rule out the roles of IDO-1 in the formation of M1-like macrophages, but they cast doubt on the robust anti-inflammatory effects of IDO inhibitors in the macrophage-mediated immune response.

scholarly journals Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1105-1108
Author(s):  
M Wieser ◽  
R Bonifer ◽  
W Oster ◽  
A Lindemann ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blot Hybridization ◽  
Interleukin 4 ◽  
Northern Blot Hybridization ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Activated Monocytes ◽  
Culture Supernatants

T cells are known to interact cooperatively with monocytes to produce Colony-Stimulating Factors (CSF), although T cell-mediated signals leading to CSF secretion by monocytes are not completely understood. We have made use of Northern blot hybridization and specific bioassays to study the effects of the T cell product interleukin-4 (IL-4) on monocyte CSF expression. The results suggest a previously unrecognized role of IL-4 as a CSF inducer since exposure of monocytes to IL-4 resulted in accumulation of transcripts for granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF). Consequently, IL-4-activated monocytes released factors in their culture supernatants biologically and antigenically indistinguishable from G- and M-CSF.

scholarly journals Hyphae and Yeasts of Candida albicans Differentially Regulate Interleukin-12 Production by Human Blood Monocytes: Inhibitory Role of C. albicans Germination

2001 ◽  
Vol 69 (7) ◽  
pp. 4695-4697 ◽  
Author(s):  
Liming Liu ◽  
Kefei Kang ◽  
Masakazu Takahara ◽  
Kevin D. Cooper ◽  
Mahmoud A. Ghannoum
Keyword(s):  
Candida Albicans ◽  
Human Blood ◽  
Critical Role ◽  
Interleukin 12 ◽  
Blood Monocytes ◽  
Inhibitory Role

ABSTRACT The role of Candida albicans yeast-to-hypha transition in interleukin-12 (IL-12) production by monocytes was investigated. Germinating C. albicans not only failed to induce IL-12 p70 but also suppressed IL-12 production induced by heat-killed C. albicans. Comparison of the abilities of germinating C. albicans and agerminating mutants to inhibit IL-12 production showed that germination of C. albicans plays a critical role in the inhibition of IL-12 production.

scholarly journals Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1105-1108 ◽  
Author(s):  
M Wieser ◽  
R Bonifer ◽  
W Oster ◽  
A Lindemann ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blot Hybridization ◽  
Interleukin 4 ◽  
Northern Blot Hybridization ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Activated Monocytes ◽  
Culture Supernatants

Abstract T cells are known to interact cooperatively with monocytes to produce Colony-Stimulating Factors (CSF), although T cell-mediated signals leading to CSF secretion by monocytes are not completely understood. We have made use of Northern blot hybridization and specific bioassays to study the effects of the T cell product interleukin-4 (IL-4) on monocyte CSF expression. The results suggest a previously unrecognized role of IL-4 as a CSF inducer since exposure of monocytes to IL-4 resulted in accumulation of transcripts for granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF). Consequently, IL-4-activated monocytes released factors in their culture supernatants biologically and antigenically indistinguishable from G- and M-CSF.

scholarly journals Demonstration of a human pyrogen-inducing factor during mixed leukocyte reactions.

1981 ◽  
Vol 153 (5) ◽  
pp. 1215-1224 ◽  
Author(s):  
C A Dinarello
Keyword(s):  
Human Blood ◽  
Mononuclear Cells ◽  
Thymidine Incorporation ◽  
Cell Concentration ◽  
Mixed Leukocyte Reaction ◽  
Blood Monocytes ◽  
Donor Cells ◽  
Blood Mononuclear Cells ◽  
Sepharose 4B

The role of lymphocytes in the pathogenesis of fever was investigated by stimulating human blood mononuclear cells in a two-way mixed leukocyte reaction (MLR). After 2-7 d of incubation, MLR supernates contained a factor that was not pyrogenic itself when injected into rabbits; however, these supernates, when incubated with human blood monocytes from a third donor, induced the synthesis of LP. The pyrogen-inducing activity was stable at 56 degrees C, destroyed at 70 degrees C, and was neither dialyzable nor removable by adsorption by anti-human leukocytic pyrogen (LP) attached to Sepharose 4B. Production of this factor was not always correlated with increased thymidine incorporation in the MLR. Its production was absent when peripheral lymphocytes were purified over nylon wool. The concentration of mononuclear cells in the MLR varied from 5 X 10(5) to 5 X 10(6)/ml in round-bottomed tubes. Under the latter conditions, some donor cells produced this factor without stimulation in the MLR culture, but when these cells were cultured on flat-bottomed containers at low cell concentration, autologous production was not observed. These experiments demonstrate the production of a human lymphocyte factor (lymphokine) that induces LP synthesis. This pyrogen-inducing lymphokine may be important in the pathogenesis of fever in certain immunologically mediated diseases.

scholarly journals Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

2020 ◽  
Vol 21 (13) ◽  
pp. 4733
Author(s):  
Shahzad Nawaz Syed ◽  
Andreas Weigert ◽  
Bernhard Brüne
Keyword(s):  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Inflammasome Activation ◽  
Relative Contribution ◽  
Mouse Macrophages ◽  
Sphingosine Kinases ◽  
Transcriptional Induction ◽  
Human And Mouse ◽  
Inflammasome Activity

Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.

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