IL-6 blocks a discrete early step in lymphopoiesis

Abstract Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis. These effects are mediated at least in part by elevated levels of interleukin 6 (IL-6). Here, we show the lymphopoiesis block in SHIP–/– mice is due to suppression of the lymphoid lineage choice by uncommitted progenitors. The suppression can be reproduced in vitro with recombinant IL-6, and IL-6 acts directly on hematopoietic progenitors. The block is partially overcome in SHIP–/– IL-6–/– double-deficient animals. IL-6 does not suppress but actually enhances proliferation of lymphoid-committed progenitors, indicating the IL-6 target cells are hematopoietic stem cells or multipotent progenitors. The findings suggest a mechanism for the lymphopenia that accompanies proinflammatory diseases.

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A Dual Role for Src Homology 2 Domain–Containing Inositol-5-Phosphatase (Ship) in Immunity

Journal of Experimental Medicine ◽

10.1084/jem.191.5.781 ◽

2000 ◽

Vol 191 (5) ◽

pp. 781-794 ◽

Cited By ~ 115

Author(s):

Cheryl D. Helgason ◽

Christian P. Kalberer ◽

Jacqueline E. Damen ◽

Suzanne M. Chappel ◽

Nicolas Pineault ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Lymphoid Development ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

B Lymphoid

In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation. SHIP−/− mice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor B (fraction C) and immature B cells in the bone marrow. In vitro, purified SHIP−/− B cells exhibit enhanced proliferation in response to B cell receptor stimulation in both the presence and absence of Fcγ receptor IIB coligation. This enhancement is associated with increased phosphorylation of both mitogen-activated protein kinase and Akt, as well as with increased survival and cell cycling. SHIP−/− mice manifest elevated serum immunoglobulin (Ig) levels and an exaggerated IgG response to the T cell–independent type 2 antigen trinitrophenyl Ficoll. However, only altered B cell development was apparent upon transplantation into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice. The in vitro hyperresponsiveness, together with the in vivo findings, suggests that SHIP regulates B lymphoid development and antigen responsiveness by both intrinsic and extrinsic mechanisms.

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Leishmania EF-1α Activates the Src Homology 2 Domain Containing Tyrosine Phosphatase SHP-1 Leading to Macrophage Deactivation

Journal of Biological Chemistry ◽

10.1074/jbc.m209210200 ◽

2002 ◽

Vol 277 (51) ◽

pp. 50190-50197 ◽

Cited By ~ 98

Author(s):

Devki Nandan ◽

Taolin Yi ◽

Martin Lopez ◽

Crystal Lai ◽

Neil E. Reiner

Keyword(s):

Leishmania Donovani ◽

Tyrosine Phosphatase ◽

Elongation Factor ◽

Host Protein ◽

Src Homology 2 ◽

Infected Cells ◽

Src Homology ◽

Src Homology 2 Domain

The human leishmaniasis are persistent infections of macrophages caused by protozoa of the genusLeishmania.The chronic nature of these infections is in part related to induction of macrophage deactivation, linked to activation of the Src homology 2 domain containing tyrosine phosphatase-1 (SHP-1) in infected cells. To investigate the mechanism of SHP-1 activation, lysates ofLeishmania donovanipromastigotes were subjected to SHP-1 affinity chromatography and proteins bound to the matrix were sequenced by mass spectrometry. This resulted in the identification ofLeishmaniaelongation factor-1α (EF-1α) as a SHP-1-binding protein. PurifiedLeishmaniaEF-1α, but not host cell EF-1α, bound directly to SHP-1in vitroleading to its activation. Three independent lines of evidence indicated thatLeishmaniaEF-1α may be exported from the phagosome thereby enabling targeting of host SHP-1. First, cytosolic fractions prepared from macrophages infected with [35S]methionine-labeled organisms containedLeishmaniaEF-1α. Second, confocal, fluorescence microscopy usingLeishmania-specific antisera detectedLeishmaniaEF-1α in the cytosol of infected cells. Third, co-immunoprecipitation showed thatLeishmaniaEF-1α was associated with SHP-1in vivoin infected cells. Finally, introduction of purifiedLeishmaniaEF-1α, but not the corresponding host protein into macrophages activated SHP-1 and blocked the induction of inducible nitric-oxide synthase expression in response to interferon-γ. Thus,LeishmaniaEF-1α is identified as a novel SHP-1-binding and activating protein that recapitulates the deactivated phenotype of infected macrophages.

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Trajectory of chemical cocktail-induced neutrophil reprogramming

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01008-8 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Yi Zhou ◽

Chuijin Wei ◽

Shumin Xiong ◽

Liaoliao Dong ◽

Zhu Chen ◽

...

Keyword(s):

Cell Types ◽

Lymphoid Cells ◽

Great Promise ◽

Target Cells ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Multipotent Progenitors ◽

First Time

AbstractHematopoietic reprogramming holds great promise for generating functional target cells and provides new angle for understanding hematopoiesis. We reported before for the first time that diverse differentiated hematopoietic cell lineages could be reprogrammed back into hematopoietic stem/progenitor cell-like cells by chemical cocktail. However, the exact cell types of induced cells and reprogramming trajectory remain elusive. Here, based on genetic tracing method CellTagging and single-cell RNA sequencing, it is found that neutrophils could be reprogrammed into multipotent progenitors, which acquire multi-differentiation potential both in vitro and in vivo, including into lymphoid cells. Construction of trajectory map of the reprogramming procession shows that mature neutrophils follow their canonical developmental route reversely into immature ones, premature ones, granulocyte/monocyte progenitors, common myeloid progenitors, and then the terminal cells, which is stage by stage or skips intermediate stages. Collectively, this study provides a precise dissection of hematopoietic reprogramming procession and sheds light on chemical cocktail-induction of hematopoietic stem cells.

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Expansion of multipotent and lymphoid-committed human progenitors through intracellular dimerization of Mpl

Blood ◽

10.1182/blood-2007-08-107466 ◽

2008 ◽

Vol 111 (8) ◽

pp. 4064-4074 ◽

Cited By ~ 14

Author(s):

Hisham Abdel-Azim ◽

Yuhua Zhu ◽

Roger Hollis ◽

Xiuli Wang ◽

Shundi Ge ◽

...

Keyword(s):

Stem Cells ◽

Intracellular Signaling ◽

Cytokine Receptor ◽

Target Cells ◽

Hematopoietic Progenitors ◽

Dimerization Domain ◽

Hematopoietic Stem ◽

Immunodeficient Mice

AbstractSelf-renewal capacity is rapidly lost during differentiation of hematopoietic stem cells to lineage-committed progenitors. We demonstrate here that regulated intracellular signaling through the cytokine receptor Mpl induces profound expansion of not only multipotent (ie, lymphomyeloid) but also lymphoid-committed human hematopoietic progenitors. A fusion protein containing the intracellular signaling domain of Mpl and a dimerization domain was constitutively expressed in populations enriched in human lymphomyeloid progenitor/stem cells (CD34+CD38−Lin−CD7−) and multilymphoid progenitors (CD34+CD38−Lin−CD7+). Intracellular dimerization of Mpl in target cells was induced by in vitro or in vivo administration of a diffusible synthetic ligand. In vitro, Mpl dimerization produced divisions of clonogenic, multilineage CD34+ cells able to engraft immunodeficient mice. When dimerization was induced in vivo after transplantation of either lymphomyeloid or multilymphoid progenitors, donor-derived hematopoiesis was sustained for at least 12 weeks and primitive CD34+Lin− progenitors were expanded more than 1000-fold. Lineage potential of progenitors was not altered and differentiation was not prevented by synthetically induced Mpl signaling. These data demonstrate that dimerization of a single cytokine receptor can deliver a profound expansion signal in both uncommitted and lymphoid-committed human hematopoietic progenitors.

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SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000645 ◽

2019 ◽

Vol 7 (1) ◽

pp. e645 ◽

Cited By ~ 4

Author(s):

Saif Huda ◽

Michelangelo Cao ◽

Anna De Rosa ◽

Mark Woodhall ◽

Pedro M. Rodriguez Cruz ◽

...

Keyword(s):

Myasthenia Gravis ◽

Cluster Formation ◽

Inhibitory Effect ◽

C2c12 Myotubes ◽

Achr Cluster ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

Achr Clustering

ObjectiveTo determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).MethodsThe effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.ResultsIn the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.ConclusionsStimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.

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Inhibition of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Reduces the Severity of Collagen-Induced Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.080369 ◽

2008 ◽

Vol 35 (12) ◽

pp. 2316-2324 ◽

Cited By ~ 3

Author(s):

KONAGI TANAKA ◽

TATSUYA HORIKAWA ◽

SATSUKI SUZUKI ◽

KAZUTAKA KITAURA ◽

JUNKO WATANABE ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Type Ii Collagen ◽

Spleen Cells ◽

Collagen Induced Arthritis ◽

Antibody Treatment ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

ObjectiveTo investigate whether the blockade of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) has any therapeutic effects on rheumatoid arthritis.MethodsA functional blocking monoclonal antibody for SHPS-1 (anti-SHPS-1 mAb) was administered at various doses to collagen-induced arthritis (CIA) mice, and severity of the arthritis was evaluated by clinical and histological scores of the limbs. To clarify the mechanisms of action of the antibody, the serum concentration of anti-type II collagen antibody was measured in those mice, and in vitro experiments were conducted to determine the effects of the antibody on the induction of osteoclasts and the release of cytokines from mouse spleen cells.ResultsCompared with mice given control IgG, the administration of anti-SHPS-1 mAb significantly reduced the severity of inflammation and destruction of bone and cartilage in CIA mice. This therapeutic effect was observed even when the antibody treatment was started after the onset of arthritis. The appearance of anti-type II collagen antibody in CIA mice was not altered by the antibody treatment. In in vitro experiments, the anti-SHPS-1 mAb significantly inhibited osteoclastogenesis of bone marrow cells, and significantly reduced the release of interleukin 1β (IL-1β), IL-2, IL- 12, interferon-γ, and tumor necrosis factor-α, but not that of IL-4 or IL-10, from the spleen cells after stimulation with concanavalin A.ConclusionAdministration of a monoclonal antibody for SHPS-1 reduced the severity of arthritis in CIA mice. Regulation of biological functions of SHPS-1 may be a novel and potent strategy to treat patients with rheumatoid arthritis.

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