SHIP Represses the Generation of Alternatively Activated Macrophages

Rauh, Michael J.; Ho, Victor W.; Pereira, Carla; Sham, Anita; Sly, Laura M.; Lam, Vivian; Huxham, Lynsey A.; Minchinton, Andrew I.; Mui, Alice; Krystal, Gerald

doi:10.1016/j.immuni.2005.09.003

Cited by 257 publications

(284 citation statements)

References 57 publications

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“…In this regard, we recently reported that SHIP, which is a potent negative regulator of the PI3K pathway in hematopoietic cells (14,15), represses the generation of M2 M s (16). This suggests that enhanced activation of the PI3K pathway facilitates M2 skewing in vivo and, consistent with this, we found that in vivo tumor growth is significantly faster in SHIP Ϫ/Ϫ mice and that tumor-infiltrated M s in these mice display a strong M2 phenotype (16).…”

supporting

confidence: 86%

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Kuroda

Rüschmann

et al. 2009

The Journal of Immunology

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102

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There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (Mφs) because of the opposing effects that these two Mφ subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine Mφ progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin−) SHIP−/− bone marrow (BM) cells induces high levels of the M2 markers, arginase I, and Ym1 in the resulting mature Mφs. These in vitro-derived mature Mφs also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-γ and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5−/− BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6−/− BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP−/− Lin− BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin− BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within Mφs themselves but by inhibiting IL-4 production from basophils.

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supporting

confidence: 86%

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Kuroda

Rüschmann

et al. 2009

The Journal of Immunology

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102

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“…Secondly, since HS and heparin are physiological ligands to Ym1 (Chang et al, 2001), it may be speculated that changes in HS turnover affect Ym1 aggregation and crystallization. Finally, Ym1 is selectively expressed by alveolar macrophages and immature neutrophils under normal conditions (Nio et al, 2004) and is only expressed by peritoneal macrophages upon LPS-stimulation (Hung et al, 2002) or differentiation into alternatively activated macrophages (Kreider et al, 2007;Rauh et al, 2005). The selective expression of Ym1 in alveolar, but not peritoneal macrophages is well in line with the appearance of granule-like structures only in the former cell type.…”

Section: Discussionmentioning

confidence: 97%

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Waern

Jia

Pejler

et al. 2010

Molecular Immunology

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Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse -/-) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse-/-mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes fromHpse -/-mice displayed normal morphology, Hpse -/-alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm.Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular

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“…2,3 Recently, it was reported that macrophages isolated from SHIP-1 −/− mice display an alternatively activated (M2) phenotype, suggesting that SHIP-1 is a negative regulator of M2 generation. 22 However, the nature of the inflammation, the cell types infiltrating the lung, and the pathologic changes in the lung are not clear. Furthermore, whether SHIP-1 plays a role in regulating the T H 2 signaling pathway, particularly IL-4 receptor-mediated signaling, is not clear.…”

Section: Discussionmentioning

confidence: 99%

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Zheng

Bailey

et al. 2007

Journal of Allergy and Clinical Immunology

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Background-Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the T H 2 activation pathway has not been established. SHIP-1 −/− mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis.

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SHIP Represses the Generation of Alternatively Activated Macrophages

Cited by 257 publications

References 57 publications

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

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