Interferon gamma induces actin polymerization, Rac1 activation and down regulates phagocytosis in human monocytic cells

Frausto-Del-Río, Dulce A.; Soto‐Cruz, Isabel; Garay-Canales, Claudia; Ambriz, Xóchitl; Soldevila, Gloria; Carretero‐Ortega, Jorge; Vázquez‐Prado, José; Ortega, Enrique

doi:10.1016/j.cyto.2011.11.008

Cited by 25 publications

(27 citation statements)

References 42 publications

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“…Usually, it is presumed that changes in the expression level of a given receptor results in corresponding changes in the magnitude of the responses mediated by the receptor. However, we (19) and others (20, 21) have reported a lack of correlation between changes in expression levels of FcγRs and phagocytosis or antibody-mediated cell cytotoxicity mediated by them. To test the hypothesis that the ability of a cell to perform specific receptor-mediated functions depends more on the polarization state of the cell than on the expression level of the receptor, we activated human macrophages to three distinct functional phenotypes and comparatively determined the expression levels of FcγRs and CD13, as well as phagocytosis and ROS production mediated by these receptors.…”

Section: Introductionmentioning

confidence: 65%

Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression

Elizabeth

Ortega

2017

Front. Immunol.

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In response to microenvironmental cues, macrophages undergo a profound phenotypic transformation acquiring distinct activation phenotypes ranging from pro-inflammatory (M1) to anti-inflammatory (M2). To study how activation phenotype influences phagocytosis and production of reactive oxygen species (ROS) mediated by receptors for IgG antibodies (Fcγ receptors) and by CD13, human monocyte-derived macrophages were polarized to distinct phenotypes using IFN-γ (Mϕ-IFN-γ), IL-4 (Mϕ-IL-4), or IL-10 (Mϕ-IL-10). Phenotypically, Mϕ-IFN-γ were characterized as CD14+CD80+CD86+ cells, Mϕ-IL-4 as CD209highCD206+CD11b+CD14low, and Mϕ-IL-10 as CD16+CD163+ cells. Compared to non-polarized macrophages, FcγRI expression increased in Mϕ-IFN-γ and Mϕ-IL-10 and FcγRIII expression increased in Mϕ-IL-10. None of the polarizing cytokines modified FcγRII or CD13 expression. Functionally, we found that cytokine-mediated activation significantly and distinctively affected FcγR- and CD13-mediated phagocytosis and ROS generation. Compared to non-polarized macrophages, FcγRI-, FcγRII-, and CD13-mediated phagocytosis was significantly increased in Mϕ-IL-10 and decreased in Mϕ-IFN-γ, although both cytokines significantly upregulated FcγRI expression. IL-10 also increased phagocytosis of Escherichia coli, showing that the effect of IL-10 on macrophage phagocytosis is not specific for a particular receptor. Interestingly, Mϕ-IL-4, which showed poor FcγR- and CD13-mediated phagocytosis, showed very high phagocytosis of E. coli and zymosan. Coupled with phagocytosis, macrophages produce ROS that contribute to microbial killing. As expected, Mϕ-IFN-γ showed significant production of ROS after FcγRI-, FcγRII-, or CD13-mediated phagocytosis. Unexpectedly, we found that Mϕ-IL-10 can also produce ROS after simultaneous stimulation through several phagocytic receptors, as coaggregation of FcγRI/FcγRII/CD13 induced a belated but significant ROS production. Together, these results demonstrate that activation of macrophages by each cytokine distinctly modulates expression of phagocytic receptors, FcγR- and CD13-mediated phagocytosis, and ROS production.

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Section: Introductionmentioning

confidence: 65%

Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression

Elizabeth

Ortega

2017

Front. Immunol.

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“…Evidence of IFN-γ-stimulated morphological changes has been found in the case of monocytes where enhanced actin polymerization was observed in the presence of IFN-γ (34). In other cell types (HepG2 and HeLa), differences in cell adhesion signaling (drug and matrix-induced) that led to adoption of distinct morphologies were discovered to significantly impact IFN-γ signaling as actin cytoskeletal arrangement was directly linked to STAT1 dephosphorylation (35).…”

Section: Morphological Features Of Mscs After Ifn-γ Stimulation Corrementioning

confidence: 80%

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

Klinker

Marklein

Surdo

et al. 2017

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

168

166

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Human mesenchymal stromal cell (MSC) lines can vary significantly in their functional characteristics, and the effectiveness of MSCbased therapeutics may be realized by finding predictive features associated with MSC function. To identify features associated with immunosuppressive capacity in MSCs, we developed a robust in vitro assay that uses principal-component analysis to integrate multidimensional flow cytometry data into a single measurement of MSC-mediated inhibition of T-cell activation. We used this assay to correlate single-cell morphological data with overall immunosuppressive capacity in a cohort of MSC lines derived from different donors and manufacturing conditions. MSC morphology after IFN-γ stimulation significantly correlated with immunosuppressive capacity and accurately predicted the immunosuppressive capacity of MSC lines in a validation cohort. IFN-γ enhanced the immunosuppressive capacity of all MSC lines, and morphology predicted the magnitude of IFN-γ-enhanced immunosuppressive activity. Together, these data identify MSC morphology as a predictive feature of MSC immunosuppressive function.H uman mesenchymal stromal cells (MSCs) can potently suppress immune responses in vitro and in animal models of human disease (1, 2), but to date MSC-based therapies have produced mixed results in clinical trials for treatment of inflammatory and autoimmune diseases (3, 4). A major challenge in the development of consistently effective MSC-based immunosuppressive therapies is that MSC lines derived from different donors and manufacturing processes (i.e., cell expansion) can possess markedly dissimilar immunosuppressive function (3,5,6). Although methods exist to assess MSC immunosuppression in vitro, they are often based on only a few measured outcomes, assay culture conditions, and donor MSC samples (5, 7-9). To improve upon these methods, we developed an experimental and analytical approach to quantify MSC-mediated immune suppression using principal-component analysis (PCA) to integrate multiple measurements of T-cell activation assessed at a range of MSC densities. This approach allowed us to determine a single value for immunosuppressive capacity for MSC lines derived from two different manufacturing processes and 13 independent donors.Another major challenge associated with MSC-based immune therapies is the lack of well-defined predictive markers to identify MSC lines with therapeutically relevant biological activities or manufacturing processes that produce more effective MSCbased products. Efforts have been made to identify MSC quality attributes associated with immunosuppression (6, 7), but the majority of clinical studies (10) rely upon the surface markers described by Dominici et al. (11). Having previously shown that morphology can predict MSC mineralization capacity (12), we hypothesized that morphological features associated with immunosuppression in MSCs could be identified and used to predict their performance in our quantitative immunosuppression assay.Using our quantitative method for as...

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“…In addition, through amplification of downstream signaling components IFNc can also enhancing adjuvant induced APC maturation and concomitant immune stimulatory antigen presentation [74,75]. Other elements of the antigen processing machinery regulated by IFNc include components of the immunoproteasome [76][77][78][79] and cytoskeletal elements that mediate trafficking of MHC/peptide complexes [64,80]. In addition to enhancing antigen presentation among professional antigen presenting cells IFNc can also allow production of MHC class II molecules in cells that do not express MHC class II antigen under steady state conditions, providing new targets for CD4+ T cell recognition and activation [81][82][83].…”

Section: Antigen Presentationmentioning

confidence: 98%

“…In addition IFNc can also induce CCR1, CCR3, and CCR5 in myeloid cells allowing recruitment of these cells to IFNc primed inflammatory sites [63]. Interestingly, IFNc signaling acts to block chemotaxis in monocytes through regulation of the actin cytoskeleton suggesting that in these cells the IFNc signal may act as a retentive factor to hold effector monocytes at the site of cytokine release [64,65].…”

Section: Modulation Of Cell Traffickingmentioning

confidence: 99%

Interferon gamma in autoimmunity: A complicated player on a complex stage

Lees

2015

Cytokine

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Early views of autoimmune disease cast IFNγ as a prototypic pro-inflammatory factor. It is now clear that IFNγ is capable of both pro- and anti-inflammatory activities with the functional outcome dependent on the physiological and pathological setting examined. Here, the major immune modulatory activities of IFNγ are reviewed and current evidence for the impact of IFNγ on pathology and regulation of several autoimmune diseases and disease models is summarized.

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Interferon gamma induces actin polymerization, Rac1 activation and down regulates phagocytosis in human monocytic cells

Cited by 25 publications

References 42 publications

Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression

Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

Interferon gamma in autoimmunity: A complicated player on a complex stage

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