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

Oh, Sun Young; Zheng, Tao; Bailey, Monica L.; Barber, Dwayne L.; Schroeder, John T.; Kim, Yoon Keun; Zhu, Zhou

doi:10.1016/j.jaci.2006.08.029

Cited by 55 publications

(65 citation statements)

References 31 publications

(32 reference statements)

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“…Although cellular infiltration was uncommon in INPP4A siRNA-treated naive mice, goblet cell metaplasia and sub-epithelial fibrosis were evident. There was a substantial increase in the activation of the PI3K-Akt signalling, which is the probable mechanism for increase in AHR, goblet cell metaplasia and collagen deposition, in line with existing evidence in which SHIP knock-out mice develop spontaneous allergic inflammation without any allergic sensitization and challenge 11 . To further confirm the protective role of INPP4A, we knocked down INPP4A by siRNA-mediated downregulation in mice with experimental asthma (Fig.…”

Section: Discussionsupporting

confidence: 87%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinase signalling output. Although inositol polyphosphate-4-phosphatase is known to regulate phosphoinositide-3 kinase signalling, little is known regarding its role in asthma pathogenesis. Here we show that modulation of inositol polyphosphate-4-phosphatase alters the severity of asthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositol polyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositol polyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpression of inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthma phenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severely aggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositol polyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airway hyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital in maintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase has an important role in modulating inflammatory response in asthma, and thus, uncover a new understanding of the complex interplay between inositol signalling and asthma, which could provide alternative strategies in asthma management. P hosphoinositide signalling, from phosphoinositide-3-kinase (PI3K) activation to Akt phosphorylation, critically regulates cellular functions, such as cell growth, differentiation, proliferation, survival and motility 1 . In response to growth factor stimuli, activation of PI(3)Ks leads to generation of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 at the plasma membrane. The intracellular concentration of PtdIns(3,4,5)P3 is controlled by a 3-phosphatase known as phosphatase and tensin homologue (PTEN) 2 or by 5-phosphatases (SHIP) 3 , resulting in the production of PtdIns(4,5)P2 and PtdIns(3,4)P2, respectively. PtdIns(3,4)P2, in turn, gets degraded by inositol polyphosphate-4-phosphatase (INPP4) to form PtdIns(3)P 4 . Genotypic variations in type I INPP4 (INPP4A), which is a regulatory checkpoint in phosphoinositide signalling, have previously been shown to be associated with increased risk of asthma 5,6 . Although other phosphoinositide phosphatases, PTEN and SHIP, have been shown to importantly regulate T-cell activation 7,8 , suppress B-cell lymphoma 9 and have protective roles in allergic airway inflammation (AAI) 10,11 , the functional role of INPP4A, in this context, is not known. As PtdIns(3,4)P2, but not PtdIns(3,4,5)P3, potently activates Akt 12 , INPP4A effectively terminates the PI3K-Akt signalling cascade.Asthma is characterized by episodic bronchoconstriction due to airway inflammation, remodelling and hyper-responsiveness 13 . Metabolic origins of asthma in obese subjects with minimal inflammatory cell infiltrate are an active topic of research 14 . Current understanding and treatment of asthma focuses on inhibiting airway inflamma...

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Section: Discussionsupporting

confidence: 87%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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“…Allergic asthma is a complex, chronic inflammatory disease of the airways and lungs. Naive Ship1 Ϫ/Ϫ mice have symptoms of allergic asthma under steady-state conditions, including severe airway inflammation, mucus hyperproduction, and airway remodeling, but the contribution of Ship1 Ϫ/Ϫ mast cells to these symptoms is unknown (14).…”

Section: Ship1 Is a Repressor Of Mastmentioning

confidence: 99%

“…Naive Ship1 Ϫ/Ϫ mice have allergic asthma-like symptoms, including severe airway inflammation, mucus hyperproduction, and symptoms of airway remodeling (14). To determine the role of Ship1 Ϫ/Ϫ mast cells in allergic asthma pathology, we induced an acute form of the disease in Ship1 Ϫ/Ϫ -BMMC-and Ship1 ϩ/ϩ -BMMC-reconstituted mice (Fig.…”

Section: Allergic Airway Inflammation Is Greater In Ship1 ϫ/ϫ -Bmmc Mmentioning

confidence: 99%

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

Haddon

Antignano

Hughes

et al. 2009

The Journal of Immunology

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SHIP1 inhibits immune receptor signaling through hydrolysis of the PI3K product phosphatidylinositol 3,4,5-trisphosphate, forming phosphatidylinositol 3,4-bisphosphate. In mast cells, SHIP1 represses FcεRI- and cytokine-mediated activation in vitro, but little is known regarding the function of SHIP1 in mast cells in vivo or the susceptibility of Ship1−/− mice to mast cell-associated diseases. In this study, we found that Ship1−/− mice have systemic mast cell hyperplasia, increased serum levels of IL-6, TNF, and IL-5, and heightened anaphylactic response. Further, by reconstituting mast cell-deficient mice with Ship1+/+ or Ship1−/− mast cells, we found that the above defects were due to loss of SHIP1 in mast cells. Additionally, we found that mice reconstituted with Ship1−/− mast cells suffered worse allergic asthma pathology than those reconstituted with Ship1+/+ mast cells. In summary, our data show that SHIP1 represses allergic inflammation and mast cell hyperplasia in vivo and exerts these effects specifically in mast cells.

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“…Recently, macrophages and dendritic cells from SHIP-1 2/2 mice have been implicated as the IL-6-overproducing cells (7,8). At a young age, SHIP-1 2/2 mice develop an inflammatory lung disease accompanied by M2 macrophage polarization reflected in chitinase crystal accumulation in alveolar macrophages and in lungs (3,4,9,10). This inflammation is progressive and leads to premature death (3,4,9,10).…”

mentioning

confidence: 99%

“…At a young age, SHIP-1 2/2 mice develop an inflammatory lung disease accompanied by M2 macrophage polarization reflected in chitinase crystal accumulation in alveolar macrophages and in lungs (3,4,9,10). This inflammation is progressive and leads to premature death (3,4,9,10). Recently, SHIP-1 2/2 mice have been reported to develop Crohn's disease, which may also impact their survival (11).…”

mentioning

confidence: 99%

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

Maxwell

Duan

Armes

et al. 2011

The Journal of Immunology

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Alternatively activated M2 macrophages are implicated as both regulators and agents of lung disease, but their control is poorly understood. SHIP-1 is a 5′ inositol phosphatase that negatively regulates the PI3K signaling pathway implicated in inflammation. SHIP-1–deficient mice have defects in hematopoiesis and B cell development, and die prematurely due to consolidation of lungs with M2-skewed macrophages. SHIP-1 is thought to restrain M2 macrophage polarization, with deregulated M2 skewing coinciding with severe lung disease in SHIP-1–deficient mice. To determine the influence of genetic background on the lung phenotype in SHIP-1−/− mice, we backcrossed the SHIP-1 null mutation onto C57BL/6 (Th2-resistant) and BALB/c (Th2-prone) backgrounds. Remarkably, we found that inflammatory lung disease was severe in C57.SHIP-1−/− mice, but absent in BALB.SHIP-1−/− mice. C57.SHIP-1−/−, but not BALB.SHIP-1−/− mice had greatly increased myeloid progenitors, myeloid hyperplasia, markedly enhanced numbers of activated alveolar macrophages, and elevated amounts of Th2 and proinflammatory cytokines in bronchoalveolar lavage fluid and serum, suggesting that deregulated cytokine production induced disease. C57.SHIP-1−/− mice also developed severe B cell-dependent autoimmune disease, which was markedly attenuated on the BALB/c background. These data demonstrate that, contrary to current concepts, loss of SHIP-1 alone is not sufficient to cause lung inflammation, with disease only manifest on a permissive genetic background. This finding questions the nature of the lung disease in SHIP-1−/− mice, suggesting that its M2 classification is not strictly correct. Future identification of disease-promoting loci might reveal determinants of comorbid lung disease and autoimmunity and uncover potentially useful therapeutic targets.

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

Cited by 55 publications

References 31 publications

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

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