scholarly journals the IKZF1-IRF4 Axis Regulates Macrophage Polarization and Macrophage-Mediated Anti-Tumor Immunity

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2514-2514 ◽  
Author(s):  
Heiko Bruns ◽  
Dimitrios Mougiakakos ◽  
Christian Bach ◽  
Martin Böttcher ◽  
Joerg Thomas Bittenbring ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Macrophage Polarization ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
M2 Macrophage ◽  
Type I ◽  
Th17 Response ◽  
Human Macrophages ◽  
M1 Phenotype

Abstract In addition to antimicrobial activity, macrophages regulate tissue development, remodeling, and repair. In terms of neoplastic growth, tumor-associated macrophages (TAMs) are even considered pro-tumorigenic based on their angiogenic and T-cell suppressive properties. In multiple myeloma (MM) macrophages represent an abundant component of the stromal cell compartment and are believed to support proliferation, survival, and drug resistance of MM cells. Those pro-tumorigenic functions are partly instructed by T-helper (TH)-2 cytokines such as interleukin-4 (IL-4) and IL-10, which skew TAM differentiation towards an alternatively activated, or so-called M2-like, phenotype. In contrast, M1 macrophages generally considered as potent effectors in response to microbial products or interferon-γ (IFN-γ), are characterized by superior antigen-presentation, abundant production of pro-inflammatory cytokines such as interleukin-12 (IL-12), and consequently, promote a polarized type I immune response against infections as well as malignant cells. Transcriptional regulation is a key determinant for macrophage polarization. The Ikaros (IKZF1) transcription factor is critical for lymphoid development and is found in all hematopoietic progenitors as well as in T-, B-, NK-cells and macrophages. Interestingly, IKZF1 is overexpressed in MM and selectively degraded by lenalidomide, which is approved in MM therapy. The potential role of IKZF1 in modulating macrophage polarization has not been elucidated yet. Here, we show that IKZF1expression is found highly elevated in M2-like macrophages and in MM TAMs. IKZF1 deletion in human macrophages by small interfering RNA (siRNA) or by lenalidomide yields an upregulation of M1-specific cytokines (IL-12 and IL-1b), chemokines (CXCL10 and CCL5), and costimulatory molecules (CD86 and CD40) and leads to a potent TH1-TH17 response. In fact, lenalidomide-pretreated macrophages display strong tumoricidal effects when co-cultured with MM cell lines as opposed to their untreated counterparts promoting MM proliferation and viability. Utilizing immunoprecipitation-sequencing (ChIP-Seq) we reveal that IKZF1 governs IRF4 and IRF5 expression in human macrophages. Recent studies demonstrate that IRF4 controls M2 macrophage polarization, while IRF5 regulates the M1 phenotype respectively. We could show that a lenalidomid-mediated M1-phenotype induction is efficiently abrogated by IRF4 overexpression or IRF5 silencing. Overall, these findings unravel a novel role for IKZF1 in orchestrating macrophage polarization via the IRF4/IRF5 pathway. Disclosures No relevant conflicts of interest to declare.

scholarly journals Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xian Jin ◽  
Tongqing Yao ◽  
Zhong’e Zhou ◽  
Jian Zhu ◽  
Song Zhang ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Advanced Glycation ◽  
Alternatively Activated Macrophages ◽  
M1 Macrophage ◽  
Glycation End Products ◽  
End Products ◽  
Patients With Diabetes ◽  
M1 Phenotype

Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.

Tet2 Is a Novel Regulator of Murine Macrophage Differentiation and Polarization

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 646-646
Author(s):  
Alyssa Cull ◽  
Brooke Snetsinger ◽  
Michael J. Rauh
Keyword(s):  
Gene Expression ◽  
Blood Plasma ◽  
Mrna Expression ◽  
Conflicts Of Interest ◽  
Environmental Influence ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Hematopoietic Stem ◽  
Arginase 1

Abstract Introduction: The epigenetic regulator, TET2, catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. Inactivating TET2 mutations are common in myeloid cancers such as chronic myelomonocytic leukemia (CMML). Although TET2 has been characterized in hematopoietic stem and progenitor cells, little is known about its role in disease-relevant monocytes/macrophages (MΦ). Previously, we found increased expression of M2 MΦ-associated arginase 1 (Arg1) in TET2 -mutant CMML and Tet2 -deficient MΦ. Therefore, our goals were to (1) characterize Tet family expression during normal murine MΦ differentiation and polarization, (2) determine the effect of Tet2 -deficiency on broader M1-M2 MΦ spectrum gene signatures. Methods: Hematopoietic-specific Tet2+/- and Tet2-/- knockout mice were generated by breeding floxed Tet2(f/f) with Vav-Cre mice (JAX), in accordance with Queen's University's Animal Care protocols. MΦs obtained by peritoneal lavage (PMΦ) and bone marrow differentiation (BMMΦ) from 9-13 week old Tet2-/- and 20-40 week old Tet2+/- mice were treated with an M1 stimulus (100ng/mL LPS) or an M2 stimulus (10ng/mL Il-4). Comparative gene expression analysis was conducted using a 591 candidate gene Mouse Immunology Gene Expression CodeSet (NanoString). Blood plasma samples collected from Tet2f/f and Tet2-/- mice were sent for cytokine/chemokine array analysis (Eve Technologies). Results: A survey of Tet mRNA expression in wild-type C57BL/6 mouse whole BM showed that Tet1 was most abundantly expressed, with Tet2 and Tet3 having relative abundances of 0.56±0.05 and 0.09±0.01 respectively. In contrast, Tet2 expression peaked, while Tet1 expression diminished during BMMΦ differentiation. Suggesting a functional role, loss of murine Tet2 is associated with skewed myelomonocytic differentiation (i.e. CMML phenotype). In terminally-differentiated MΦ, Tet2 was the most abundantly expressed Tet gene, suggesting MΦ-specific functions. Consistent with this, following a 3-hour LPS stimulation, Tet2 mRNA levels increased 2- to 4-fold, whereas Il-4 failed to induce a similar increase in expression. Overall, our results suggested that Tet2 plays a role in M1 but not M2 macrophage polarization. Based on these findings, we hypothesized that loss of Tet2 would lead to M1 program dysregulation. PMΦs were obtained from Tet2f/f and Tet2-/- mice (n=2/ genotype) and RNA was harvested from untreated and LPS- or Il-4-treated cells. Pools of these RNA samples were then screened using Nanostring. Overall, M1-associated markers such as Stat1, Socs1, Nfkbiz, Il-6, Il-27, Il-12, Il-1 and Ccl2 were markedly increased by 2- to 50-fold in resting Tet2-/- PMΦs compared to matched Tet2f/f samples. These same M1 genes demonstrated a reduced ability to be induced by LPS treatment. We also found that while the expression of most M2 genes was similar in controls versus knockouts, Il-1rn and Arg1 were overexpressed, and Marco was decreased. This suggested that Tet2 -deficient MΦs possess a complex phenotype with a potential homeostatic response to M1 gene dysregulation. We have previously seen variable upregulation of Arg1 in mouse BMMΦs and PMΦs. Approximately 60% of Tet2-deficient mice (+/- and -/-) (n=20) tested for MΦ Arg1 mRNA expression demonstrated 2- to 90-fold increases in Arg1 compared to pooled Tet2f/f controls (n=5). We were interested in investigating the underlying mechanisms contributing to this dramatic increase in expression. Using Nanostring on pooled Tet2-deficient PMΦs with low (n=7) or high (n=8) Arg1 mRNA expression, we were able to identify genes whose expression significantly correlated with Arg1 overexpression: Cxcl3 (p=0.0329), Ppbp (p=0.0015), Cxcl1 (p=0.0104) and Ccl6 (p=0.0185). Of note, Ppbp was the most divergently expressed gene (46-fold difference) in Arg1 low vs Arg1 high macrophages, followed by Arg1 itself (14-fold difference). Suggesting a further environmental influence, blood plasma levels of TNF-alpha, Il-1b, Il-4, Il-10, Il-12 and Il-13 were significantly elevated in mice with high PMΦ Arg1 mRNA expression (n=5) compared to those with low expression (n=10). Conclusions: Tet2 is a novel regulator of murine MΦ, induced during MΦ differentiation and M1-polarization. Tet2 loss leads to complex disruption of the M1-M2 spectrum. We are currently exploring whether human TET2 mutations contribute to the abnormal immune environment of myeloid cancers. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interleukin-4 supports interleukin-12-induced proliferation and interferon-γ secretion in human activated lymphoblasts and T helper type 1 cells

Immunology ◽  
2006 ◽  
Vol 119 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Martin A. Kriegel ◽  
Theresa Tretter ◽  
Norbert Blank ◽  
Martin Schiller ◽  
Christoph Gabler ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
T Helper ◽  
Helper Type

Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization

ChemBioChem ◽  
2016 ◽  
Vol 17 (22) ◽  
pp. 2123-2128 ◽  
Author(s):  
Tessa Lühmann ◽  
Valerie Spieler ◽  
Vera Werner ◽  
Marie-Gabrielle Ludwig ◽  
Juliane Fiebig ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Interleukin 4 ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

scholarly journals TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization

2022 ◽  
Vol 10 (1) ◽  
pp. e003571
Author(s):  
Alycia Gardner ◽  
Álvaro de Mingo Pulido ◽  
Kay Hänggi ◽  
Sarah Bazargan ◽  
Alexis Onimus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Γ ◽  
Response To Therapy ◽  
Interleukin 12 ◽  
Type I ◽  
T Cell Infiltration ◽  
Blocking Antibodies ◽  
Bone Marrow Chimeras

BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

Harnessing the immune response to improve functional healing

2018 ◽  
Vol 10 (463) ◽  
pp. eaav3889 ◽  
Author(s):  
Julianne L. Holloway
Keyword(s):  
Immune Response ◽  
Gold Nanoparticles ◽  
Mouse Model ◽  
Macrophage Polarization ◽  
Interleukin 4 ◽  
M2 Macrophage ◽  
Muscle Recovery ◽  
M2 Macrophage Polarization

Interleukin-4–conjugated gold nanoparticles promote M2 macrophage polarization and functional muscle recovery in an ischemic mouse model.

scholarly journals Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yu ◽  
Shucheng Gan ◽  
Qingchen Zhu ◽  
Dongfang Dai ◽  
Ni Li ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Regulatory Mechanism ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Creb Binding Protein ◽  
Human Macrophages ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
Negative Regulatory Mechanism

Abstract Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.

scholarly journals Regulation of Epigenetic Modifiers, Including KDM6B, by Interferon-γ and Interleukin-4 in Human Macrophages

2017 ◽  
Vol 8 ◽  
Author(s):  
Gökçe Yıldırım-Buharalıoğlu ◽  
Mark Bond ◽  
Graciela B. Sala-Newby ◽  
Charles C. T. Hindmarch ◽  
Andrew C. Newby
Keyword(s):  
Interferon Γ ◽  
Interleukin 4 ◽  
Human Macrophages ◽  
Epigenetic Modifiers

scholarly journals The Effect of Zearalenone on the Cytokine Environment, Oxidoreductive Balance and Metabolism in Porcine Ileal Peyer’s Patches

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 350
Author(s):  
Kazimierz Obremski ◽  
Wojciech Trybowski ◽  
Paweł Wojtacha ◽  
Magdalena Gajęcka ◽  
Józef Tyburski ◽  
...  
Keyword(s):  
Stress Responses ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Basal Metabolism ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
Factor Α

The aim of the present study was to determine the effect of zearalenone (ZEN), administered per os to gilts at doses equivalent to 50%, 100%, and 150% of no-observed-adverse-effect level (NOAEL) values for 14, 28, and 42 days during weaning, on changes in the parameters of the oxidoreductive balance, cytokine secretion, and basal metabolism in ileal Payer’s patches. Immunoenzymatic ELISA tests and biochemical methods were used to measure the concentrations of interleukin 1α, interleukin 1β, interleukin 12/23p40, interleukin 2, interferon γ, interleukin 4, interleukin 6, interleukin 8, tumor necrosis factor α, interleukin 10, transforming growth factor β, malondialdehyde, sulfhydryl groups, fructose, glucose, and proline, as well as the activity of peroxidase, superoxide dismutase and catalase. The study demonstrated that ZEN doses corresponding to 50%, 100%, and 150% of NOAEL values, i.e., 5 µg, 10 µg, and 15 µg ZEN/kg BW, respectively, have proinflammatory properties, exacerbate oxidative stress responses, and disrupt basal metabolism in ileal Payer’s patches in gilts.

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