Regulation of hematopoietic cell signaling by SHIP-1 inositol phosphatase: growth factors and beyond

Hibbs, Margaret L.; Raftery, April L.; Tsantikos, Evelyn

doi:10.1080/08977194.2019.1569649

Cited by 16 publications

(15 citation statements)

References 147 publications

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“…This may be determined by the specific disease‐associated genetic mutations present. For example, SHIP‐1‐deficient mice represent another lupus model with systemic inflammation, elevated G‐CSF levels, enhanced extramedullary hematopoiesis, and myeloid cell expansion 40 . Although many of these features are dependent on the presence of G‐CSF, loss of G‐CSF did not rescue autoimmunity, as SHIP‐1 −/− G‐CSF −/− mice exhibited activated B cells, elevated Ig levels, circulating autoantibodies, and glomerulonephritis 7 .…”

Section: Discussionmentioning

confidence: 99%

Granulocyte colony‐stimulating factor is not pathogenic in lupus nephritis

Gottschalk

Vincent

Hoi

et al. 2021

Immunity Inflam & Disease

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Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by autoantibodies that form immune complexes with self‐antigens, which deposit in various tissues, leading to inflammation and disease. The etiology of disease is complex and still not completely elucidated. Dysregulated inflammation is an important disease feature, and the mainstay of lupus treatment still utilizes nonspecific anti‐inflammatory drugs. Granulocyte colony‐stimulating factor (G‐CSF) is a growth, survival, and activation factor for neutrophils and a mobilizer of hematopoietic stem cells, both of which underlie inflammatory responses in lupus. To determine whether G‐CSF has a causal role in lupus, we genetically deleted G‐CSF from Lyn‐deficient mice, an experimental model of lupus nephritis. Lyn−/−G‐CSF−/− mice displayed many of the inflammatory features of Lyn‐deficient mice; however, they had reduced bone marrow and tissue neutrophils, consistent with G‐CSF's role in neutrophil development. Unexpectedly, in comparison to aged Lyn‐deficient mice, matched Lyn−/−G‐CSF− /− mice maintained neutrophil hyperactivation and exhibited exacerbated numbers of effector memory T cells, augmented autoantibody titers, and worsened lupus nephritis. In humans, serum G‐CSF levels were not elevated in patients with lupus or with active renal disease. Thus, these studies suggest that G‐CSF is not pathogenic in lupus, and therefore G‐CSF blockade is an unsuitable therapeutic avenue.

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Section: Discussionmentioning

confidence: 99%

Granulocyte colony‐stimulating factor is not pathogenic in lupus nephritis

Gottschalk

Vincent

Hoi

et al. 2021

Immunity Inflam & Disease

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“…We suggest that disease indications for which small molecule SHIP1 allosteric regulators are developed should be ones in which IL10 ( Friedrich et al., 2019 ; Ouyang and O'Garra, 2019 ; Ouyang et al., 2011 ) (or other physiological regulators of SHIP1) ( Hibbs et al., 2018 ; Chan et al., 2012 ; Cheung et al., 2013 ; Dobranowski and Sly, 2018 ; Pauls and Marshall, 2017 ) has been shown to play a beneficial role. These small molecules should also have similar binding properties to SHIP1 as its natural ligand PI(3,4)P 2.…”

Section: Discussionmentioning

confidence: 99%

“…The SHIP1 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase is a cytoplasmic protein expressed predominantly in hematopoietic cells ( Hibbs et al., 2018 ; Fernandes et al., 2013 #1400, Huber et al., 1999 ; Krystal, 2000 ; Pauls and Marshall, 2017 ). In response to extracellular signals, SHIP1 can be recruited to the cell membrane and one of its actions can be to turn off phosphoinositide 3-kinase (PI3K) signaling ( Brown et al., 2010 ) by dephosphorylating the PI3K product PIP 3 into PI(3,4)P 2 ( Fernandes et al., 2013 ; Huber et al., 1999 ; Krystal, 2000 ; Pauls and Marshall, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

et al. 2020

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Summary The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1 and provide a rationale for use of allosteric SHIP1-activating compounds, which mimic the beneficial anti-inflammatory actions of IL10. Video Abstract

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“…Furthermore, SHIP-1-deficient mice have augmented PI3K/AKT signaling and are prone to developing progressive lung inflammation as a result of exacerbated immune responses and enhanced macrophage activation in lung airspaces [ 166 ]. Therefore, abnormalities in SHIP-1 activity within the brain may elicit pathogenic microglia responses that drive or contribute to the development of Alzheimer’s disease [ 167 ]. Collectively, these findings indicate that dysregulation in AKT activity in microglia, brought about by defective negative regulation through changes in INPP5D , contributes to the development of Alzheimer’s disease.…”

Section: Aberrant Pi3k-akt Signaling In Microglia As a Driver Of Chronic Neuroinflammationmentioning

confidence: 99%

Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation

Chu

Mychasiuk

Hibbs

et al. 2021

J Neuroinflammation

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Microglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.

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Regulation of hematopoietic cell signaling by SHIP-1 inositol phosphatase: growth factors and beyond

Cited by 16 publications

References 147 publications

Granulocyte colony‐stimulating factor is not pathogenic in lupus nephritis

Granulocyte colony‐stimulating factor is not pathogenic in lupus nephritis

Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation

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