scholarly journals Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1

2020 ◽  
Vol 205 (6) ◽  
pp. 1580-1592
Author(s):  
Alexandra Huber ◽  
Barbara Killy ◽  
Nadine Grummel ◽  
Barbara Bodendorfer ◽  
Sushmita Paul ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Macrophage Response ◽  
Cord Factor ◽  
Ifn Γ

scholarly journals Effect of interleukin-15 on depressed splenic dendritic cell functions following trauma-hemorrhage

2009 ◽  
Vol 296 (1) ◽  
pp. C124-C130 ◽  
Author(s):  
Takashi Kawasaki ◽  
Mashkoor A. Choudhry ◽  
Martin G. Schwacha ◽  
Kirby I. Bland ◽  
Irshad H. Chaudry
Keyword(s):  
Dendritic Cell ◽  
Antigen Presentation ◽  
Ex Vivo ◽  
Sham Operation ◽  
Dc Functions ◽  
Midline Laparotomy ◽  
Shed Blood ◽  
Cell Functions ◽  
Splenic Dendritic Cell ◽  
Ifn Γ

Although trauma-hemorrhage (T-H) induces suppressed splenic dendritic cell (DC) maturation and antigen presentation capacity, it remains unclear whether IL-15 modulates splenic DC functions. The aim of this study therefore was to investigate the effect of IL-15 on splenic DC functions after T-H. Male C3H/HeN mice (6–8 wk old) were randomly assigned to T-H or sham operation. T-H was induced by midline laparotomy and ∼90 min of hemorrhagic shock (blood pressure 35 mmHg), followed by fluid resuscitation (4× the shed blood volume in the form of Ringer lactate). Two hours later, mice were killed, splenic DCs were isolated, and the effects of exogenous IL-15 on their costimulatory factors, major histocompatibility class II expression, ability to produce cytokines, and antigen presentation were measured. The results indicate that IL-15 production capacity of splenic DCs was reduced following T-H. Ex vivo exposure to IL-15 attenuated the suppressed production of TNF-α, IL-6, and IFN-γ from splenic DCs following T-H. In addition, expression of surface antigen studies demonstrate that exogenous IL-15 attenuated T-H-induced downregulation of the activation of DC. The suppressed splenic DC antigen presentation function following T-H was also attenuated by IL-15 treatment. Moreover, IL-15 enhanced IL-12-induced IFN-γ production and antigen presentation by splenic DCs. These data suggest that ex vivo treatment with IL-15 following T-H provides beneficial effects on splenic DCs. The depression in IL-15 production by splenic DCs could contribute to the host's enhanced susceptibility to infections following T-H.

A Gene Variant in IRF3 Impacts On the Clinical Outcome of Acute Myeloid Leukemia (AML) Patients Submitted to Allogeneic Stem Cell Transplantation (allo-SCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 468-468
Author(s):  
Beatriz Martin-Antonio ◽  
Maria Suarez-LLedo ◽  
Montserrat Arroyes ◽  
Francesc Fernandez-Avilés ◽  
Carmen Martinez ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Inflammatory Response ◽  
Antigen Presentation ◽  
Nk Cells ◽  
Nk Cell ◽  
Dominant Gene ◽  
Lower Number ◽  
Gene Variant ◽  
Ifn Γ ◽  
Risk Of Relapse

Abstract Abstract 468 AML is worldwide the most frequent indication for allo-SCT. This is most likely due to the curative potential of the graft versus leukemia (GVL) effect associated with the procedure. Unfortunately, GVL and GVHD are intimately linked. Thus, it is important to identify markers predictive of severe GVHD, to balance the risk of this complication and the risk of relapse in a particular AML patient. The innate immune system, as the initial regulator of the inflammatory response, mediates an important role in these reactions. After conditioning regimen, toll-like receptors initiate the innate inflammatory response by activating intracellular signaling cascades that converge on the activation of NF-κB and interferon regulatory factor-3 (IRF3). IRF3 activation in bone marrow derived dendritic cells (DCs) results in natural killer (NK) cell activation inducing an anti-tumor NK response. We hypothesized that genetic variability in IRF3 in either the donor or the recipient could impact on the degree of the inflammatory response and on GVHD and GVL effect allo-SCT. We analysed the effect of two frequent single nucleotide polymorphisms (SNPs) in IRF3 (rs7251 and rs2304205), which are inherited in a haplotype, on the GVHD and GVL in 249 patients diagnosed with AML and submitted to HLA-identical sibling allo-SCT. Those patients with a donor carrying dominant GG gene variant in rs7251 (45% of the donors) had, as compared to GC (44%) and CC (11%) variants, lower aGVHD III-IV incidence (4% vs 11% vs 27%; p=0.0078) (Figure 1A), higher relapse incidence (49% vs 35% vs 26%; p=0.018) (Figure 1B), and lower TRM (7% vs 24% vs 18%; p=0.0065). This clinical impact on severe aGVHD, relapse, and TRM was retained at multivariate analysis. Further, GG gene variant in rs7251 when present in the patient was also associated with lower aGVHD III-IV incidence (4% vs 13% vs 24%; p=0.009), higher relapse incidence (50% vs 34% vs 31%; p=0.014), and with a trend for a lower TRM (9% vs 19% vs 23%; p=0.064). Patients carrying AA dominant gene variant in rs2304205 in IRF3 presented a higher relapse incidence than the rest of genotypes (50% vs 39% vs 18%, p=0.0068). However, this impact was not retained at multivariate analysis. Functional studies in 180 healthy individuals showed that after stimulation of peripheral blood with cytomegalovirus (CMV) peptides, GG gene variant in rs7251 presented lower IFN-γ serum production than the rest of individuals, and GG gene variant was associated with lower number of IFN-γ producing mature NK cells, lower number of cytotoxic NK cells against K562 cell line and lower proliferation of T cells after antigen presentation by DCs. In conclusion, we show that a particular gene variant in IRF3 in the donors is associated with a low incidence of severe aGVHD and high incidence of relapse in AML patients submitted to allo-SCT. This finding could be explained by its effect in the inflammatory and adaptive immune response, with lower IFN-g production, lower lymphocyte proliferation after antigen presentation by DCs and lower mature NK cell response. Thus, these results suggest that, if possible, when transplanting an AML patient with a low risk of relapse it might be preferable to select a donor harbouring GG in rs7251 in IRF3, and when transplanting an AML patient with a high risk of relapse after the transplant it might be preferable to consider select a donor GC or CC in rs7251 in IRF3. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IFN-γ Expressed by T Cells Regulates the Persistence of Antigen Presentation by Limiting the Survival of Dendritic Cells

2009 ◽  
Vol 183 (12) ◽  
pp. 7710-7718 ◽  
Author(s):  
Marsha S. Russell ◽  
Renu Dudani ◽  
Lakshmi Krishnan ◽  
Subash Sad
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Antigen Presentation ◽  
Ifn Γ

scholarly journals NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Susana López-López ◽  
María José Romero de Ávila ◽  
Natalia Carolina Hernández de León ◽  
Francisco Ruiz-Marcos ◽  
Victoriano Baladrón ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Macrophage Activation ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Regulatory Element ◽  
Interferon Γ ◽  
Negative Regulator ◽  
Signal Pathways ◽  
Macrophage Response ◽  
Ifn Γ

NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1. Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation.

scholarly journals Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor

2009 ◽  
Vol 182 (5) ◽  
pp. 3155-3164 ◽  
Author(s):  
Bárbara Acosta-Iborra ◽  
Ainara Elorza ◽  
Isabel M. Olazabal ◽  
Noa B. Martín-Cofreces ◽  
Silvia Martin-Puig ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Antigen Presentation ◽  
Oxygen Sensing ◽  
Ifn Γ

Abstract 3689: Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Koichi Shimizu ◽  
Peter Libby ◽  
Viviane Z Rocha ◽  
Eduardo J Folco ◽  
Rica Shubiki ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Antigen Presentation ◽  
Allograft Rejection ◽  
Cardiac Transplantation ◽  
Cardiac Allograft ◽  
Mrna Levels ◽  
Acute Allograft Rejection ◽  
Cardiac Allograft Rejection ◽  
Ifn Γ

Background: The S100 calcium-binding proteins MRP-8 (S100A8) and MRP-14 (S100A9) heterodimerize to form MRP-8/14 complexes that regulate myeloid cell function, control inflammatory responses, and serve as an early serum marker for monitoring acute allograft rejection. Despite functioning as a putative pro-inflammatory mediator, the pathophysiological role of MRP-8/14 in cardiovascular disease remains unknown. This study used murine cardiac transplantation to investigate the role of MRP-14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14−/−) lacking MRP-8/14 complexes. Results: In major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor hearts and C57BL/6 recipients), allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14−/ −recipients compared to > 12 weeks (n = 15, p<0.0001) in wild-type (WT) recipients. At 2 week post-transplantation, allografts in MRP14−/ − recipients had significantly higher parenchymal rejection (PR) scores (2.8 ± 0.8, n=8) than WT recipients (0.8 ± 0.8, n=12, p<0.0001). MRP14−/ − recipients had significantly increased allograft accumulation of T cells and macrophages and mRNA levels of IFN-γ and IFN-γ–associated chemokines (IP-10, Mig, and I-TAC) compared to WT recipients. The MRP14−/− recipients also had significantly more lymphocytes in draining lymph nodes than WT recipients (cell number per lymph nodes: 23.7 ± 0.7 x 105 for MRP14−/− vs. 6.0 ± 0.2 x 105 for WT, p < 0.0001). MRP14−/− dendritic cells (DC) stimulated with IFN-γ expressed significantly higher levels of the co-stimulatory molecules CD86 and ICOSL, and mixed leukocyte reaction using allo-EC-primed MRP14−/− DC resulted in significantly higher antigen-presenting function than WT DC. Conclusion: Taken together, these observations indicate that MRP-8/14 complexes participate in acute allograft rejection by modulating dendritic cell antigen presentation and T cell priming. The unexpected finding that deficiency of MRP-8/14 complexes exacerbates acute allograft rejection indicates that MRP-8/14 has distinct roles in modulating immune cell functions, such as migration and antigen presentation. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Abstract 255: Modulation Of Cardiac Macrophages As A Strategy For Infarct Healing

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Inthirai Somasuntharam ◽  
Sheridan Carroll ◽  
Milton Brown ◽  
Andres Garcia ◽  
Michael Davis
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Delivery System ◽  
Tube Formation ◽  
Interleukin 4 ◽  
Macrophage Response ◽  
Healing Response ◽  
Ifn Γ

Heart failure is the leading cause of death in the developed world and myocardial infarction (MI) is the most common cause. Macrophages are key cells that orchestrate the initial inflammatory as well as later stage wound healing responses following MI. These functions are carried out by pro-inflammatory (M1) and reparative (M2) macrophages respectively. Optimal healing response after MI requires a balancing act of the biphasic macrophage response, so as to not prolong inflammatory signals detrimental to wound healing. Taking advantage of the fact that interleukin-4 (IL-4) activates macrophages towards M2, we hypothesize that delivering IL-4 to the post-MI heart can alter the ratio of M2 to M1 macrophages in the infarct area and induce a better healing response. In this study, we validate our approach in vitro and perform in vitro optimization of a suitable delivery system. RAW 264.7 macrophages were stimulated with IL-4 (10ng/uL) or LPS/IFN-γ (100ng/mL and 10ng/mL) for 24h and gene expression markers (qPCR) and Nitric Oxide (NO) levels (Griess assay) analyzed as indication of M1or M2 activation. Mouse aortic endothelial cells were treated with conditioned media from these cells for 24h and tube formation assessed on matrigel. A bioactive, protease-cleavable polyethylene glycol (PEG) hydrogel delivery system was evaluated for release of functional IL-4 to LPS-activated macrophages. Empty or IL-4 encapsulating hydrogel was placed on a trans-well above LPS-stimulated macrophages. Collagenase I at 0.1mg/mL was applied over 48h to degrade the gels and release IL-4 (n≥3 and p<0.05 considered significant by one-way ANOVA). We demonstrate that IL-4 significantly upregulates M2 markers (MRC-1 and Arg-1) while IFN-γ and LPS upregulate M1 markers (NO and TNF-alpha). We observe enhanced tube density in endothelial cells treated with M2 media while M1 inhibited tube formation. Hydrogel release study shows a significant reduction in NO levels of LPS-stimulated macrophages when IL-4 is released, demonstrating that IL-4 is released from the gel in its bioactive form. In conclusion, we show that macrophages can indeed respond to changing stimuli and adopt distinct activation types and our PEG based hydrogel could be a potential delivery system for in vivo IL-4 delivery.

Pre-treatment with Mycobacterium avium-derived lipids reduces the macrophage response to interferon γ in BCG-vaccinated mice

2013 ◽  
Vol 62 (7) ◽  
pp. 980-987 ◽  
Author(s):  
Daqing Yang ◽  
Beiyi Liu ◽  
Xiaoriu Hou ◽  
Delong Jiao ◽  
Xueli Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Avium ◽  
Inflammatory Cells ◽  
Bactericidal Effect ◽  
Interferon Γ ◽  
Macrophage Response ◽  
Murine Macrophages ◽  
Ifn Γ ◽  
Pre Treatment ◽  
Environmental Pathogens

Mycobacterium bovis Bacille Calmette–Guérin (BCG) is the current vaccine used against Mycobacterium tuberculosis (MTB) infection. However, exposure to environmental pathogens, such as Mycobacterium avium, interferes with the immune response induced by BCG vaccination. How M. avium affects the efficiency of BCG is unclear. In this study, BCG-vaccinated mice pre-treated with M. avium-derived lipids (MALs) showed a higher mycobacterial load and increased infiltration of inflammatory cells compared to control mice treated with Escherichia coli-derived lipids (ELs). Unexpectedly, there were no changes in cell proliferation or IFN-γ levels in spleen cells stimulated with protein purified derivatives (PPD) or heat-inactivated BCG in MALs-treated mice. However, pre-treatment with MALs decreased the bactericidal effect as well as the production of TNF-α and nitric oxide (NO) in murine macrophages from BCG-vaccinated mice stimulated with IFN-γ. These results suggest that MAL pre-treatment dampens the immune response against MTB and that this dampening is associated with a decreased response to IFN-γ stimulation in murine macrophages. T-lymphocyte responses, however, were unaffected.

Endothelial cells: Heparin modulates the induction of functional antigen presentation by IFN-γ

1997 ◽  
Vol 25 (2) ◽  
pp. 195S-195S ◽  
Author(s):  
DAVID A RIX ◽  
MICHAEL S DOUGLAS ◽  
MARIA P LEON ◽  
SIMI ALI ◽  
DAVID TALBOT ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Antigen Presentation ◽  
Ifn Γ
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