<scp>MCP</scp>‐1/<scp>CCR</scp>2 interactions direct migration of peripheral <scp>B</scp> and <scp>T</scp> lymphocytes to the thymus during acute infectious/inflammatory processes

Hodge, Deborah L.; Reynolds, Della; Cerbán, Fabio M.; Correa, Silvia G.; Baez, Natalia Soledad; Young, Howard A.; Rodríguez-Galán, María Cecilia

doi:10.1002/eji.201242408

Cited by 38 publications

(32 citation statements)

References 37 publications

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“…6B). Clinical data indicated that increased levels of MCP-1/MCP-1 receptor (also referred to as CCL2/CCR2) are consistent with those found in lipopolysaccharides (LPS)-stimulated peripheral monocytes or T and B lymphocytes (Miotto et al, 2007;Hodge et al, 2012). However, whether the epithelium-derived exosomal ATF3 RNA may affect LPS induced monocyte migration is still unknown.…”

Section: Knockdown Of Atf3 Increased I/r-induced Mcp-1 Mrna Expressiomentioning

confidence: 84%

Exosomal ATF3 RNA Attenuates Pro‐Inflammatory Gene MCP‐1 Transcription in Renal Ischemia‐Reperfusion

Chen

Lai

Lan

et al. 2014

Journal Cellular Physiology

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Transcriptional repressor activating transcription factor 3 (ATF3) is induced by various stress stimuli, including inflammation-induced renal injury. In addition, ATF3 also down-regulates adhesion molecules like intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and monocyte chemotactic protein-1 (MCP-1). However, the relation between up-regulated ATF3 after renal ischemia/reperfusion (I/R) injury and MCP-1 is not completely understood. In this study, we demonstrated that, in renal I/R induced inflammation, induction of adhesion molecules (interleukin-6, P-selectin, E-selectin, ICAM, VCAM, and MCP-1) was higher in ATF3-knockout mice than in wild-type animals. Molecular and biochemical analyses revealed that ATF3 binds to the ATF/CRE sites in the MCP-1 promoter and inhibits the secretion of MCP-1 from renal epithelial cells after I/R injury. Urinary exosome containing ATF3 RNA was 60-fold higher in patients with acute kidney injury than in normal controls, but no difference in total urinary ATF3 RNA levels was found. In addition, in vitro study showed that exosome containing ATF3 RNA derived from epithelial cells also inhibits MCP-1 expression in the epithelial cells and macrophage migration. Furthermore, direct administration of the epithelium-derived exosomal ATF3 RNA attenuates I/R induced kidney injury. Together, our studies reveal a novel regulatory mechanism of MCP-1 expression mediated by the exosomal ATF3 RNA under renal I/R insult and suggest a potential targeted therapy for I/R induced acute kidney injury.

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Section: Knockdown Of Atf3 Increased I/r-induced Mcp-1 Mrna Expressiomentioning

confidence: 84%

Exosomal ATF3 RNA Attenuates Pro‐Inflammatory Gene MCP‐1 Transcription in Renal Ischemia‐Reperfusion

Chen

Lai

Lan

et al. 2014

Journal Cellular Physiology

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“…In other in vivo and in vitro studies, CCL2 was attributed more functions such as inducing apoptosis in podocytes and myocytes or directly acting on tumor cell proliferation, survival, and migration as reported in prostate cancer . Recently, a study showed that peripheral activated/memory T cells could migrate to the thymus through the CCL2/CCR2 interactions . Their thymic entry was proposed to be important for central tolerance and the maintenance of medullary epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Monocyte chemoattractant protein 1 (MCP‐1/CCL2) contributes to thymus atrophy in acute myeloid leukemia

2014

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Recent studies on acute myelogenous leukemia (AML) patients have revealed the existence of T-cell immunodeficiencies, characterized by peripheral T lymphocytes that are unable to interact with blasts, reduced thymic emigrants and oligoclonal restricted repertoires. These observations suggest that there is a profound thymic dysregulation, which is difficult to study in AML patients. Using the C1498 AML mouse model, we demonstrated that leukemia development was associated with thymus atrophy, which was defined by abnormal organ weight and reduced cellularity. In addition, we observed a dramatic loss of peripheral CD4 + and CD8 + T-cell numbers with increased frequencies of CD4 + FoxP3 + regulatory and activated/memory T cells. Investigating the mechanisms leading to this atrophy, we observed a significant accumulation of the monocyte chemoattractant protein 1 (MCP-1/CCL2) in thymi of leukemic mice. Treatment of AML-bearing animals with a blocking anti-CCL2 antibody revealed a lower tumor burden, augmented antileukemic T-cell responses, and improved survival rate compared to nontreated mice. These results were not observed when neutralization of CCL2 was performed in thymectomized mice. Altogether, we show that the CCL2 protein participates in thymic atrophy in AML mice, and this could have important implications for future immunotherapeutic strategies.Keywords: Acute myeloid leukemia r MCP-1/CCL2 r mouse model r T-cell response r thymus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAcute myeloid leukemia (AML) is characterized by impaired hematopoiesis. At the time of diagnosis and prior to chemotherapy, it has been shown that myeloid and plasmacytoid dendritic cell (DC) subsets are also affected by leukemogenesis and may exhibit the leukemic genotype. However, the myeloid-derived DCs retain their maturation capacity and ability to stimulate T lymphocytes [1]. Despite these observations, poor immune T-cell Correspondence: Dr. Carine Brinster e-mail: carine.brinster@inserm.fr responses are associated with AML in patients [2,3], and this immunodeficiency has been suggested to promote the expansion of malignant cells [4]. AML patients have normal-to-reduced levels of peripheral total CD3 + T lymphocytes that are unable to form effective immune synapses with autologous blasts [5]. Previous studies have described increased levels of circulating immunosuppressive CD4 + CD25 high regulatory T cells (Treg) in patients with untreated AML [6,7], which may contribute to the induction of tolerance to the leukemic cells. Furthermore, an altered T-cell repertoire associated with clonal expansion of certain T-cell receptor (TCR) Vβ subsets has been found in leukemic patients [8] Results Leukemia leads to thymic atrophyIn patients, the leukemic process appears to contribute to a profound state of immune suppression that affects the T-cell compartment [5]. Therefore, we investigated to what extent T-cell phenotype, function, and thymic differentiation ...

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“…A dysregulated immune response within the aortic wall is commonly accepted, at present, as a contributing factor in the development of human AAA. Lymphocyte expression of CCR2 may be important in the activation and migratory characteristics of these cells, 44 whereas the mTOR pathway is emerging as a critical regulator of T-cell, B-cell, and antigen-presenting cell differentiation, activation, and function. 45 Whether an immunosuppressant effect of everolimus on circulating and aortic lymphocyte profile (eg, T-cell subsets) played a role in limiting A2-induced aortic dilatation was not addressed here.…”

Section: Discussionmentioning

confidence: 99%

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes

Moran

Jose

Moxon

et al. 2013

ATVB

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Objective-We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E-deficient mouse model. Approach and Results-Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of interferon (IFN)-γ and IFNγ-induced CCR2 expression in apolipoprotein E-deficient mouse bone marrow monocytes. Further, everolimus diminished IFNγ/lipopolysaccharidestimulated M1 polarization in apolipoprotein E-deficient mouse bone marrow monocyte-differentiated macrophages. Conclusions-Systemic

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MCP‐1/CCR2 interactions direct migration of peripheral B and T lymphocytes to the thymus during acute infectious/inflammatory processes

Cited by 38 publications

References 37 publications

Exosomal ATF3 RNA Attenuates Pro‐Inflammatory Gene MCP‐1 Transcription in Renal Ischemia‐Reperfusion

Exosomal ATF3 RNA Attenuates Pro‐Inflammatory Gene MCP‐1 Transcription in Renal Ischemia‐Reperfusion

Monocyte chemoattractant protein 1 (MCP‐1/CCL2) contributes to thymus atrophy in acute myeloid leukemia

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes

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