Age-related impairment of GM-CSF-induced signalling in neutrophils: Role of SHP-1 and SOCS proteins

Tortorella, Cosimo; Simone, Olivia; Piazzolla, Giuseppina; Stella, Isabella; Antonaci, Salvatore

doi:10.1016/j.arr.2006.10.001

Cited by 49 publications

(31 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This conclusion is supported by the fact that Siglec-8 does not contain any known cytoplasmic signaling domains but does contain two tyrosine-based motifs, one of which appears to contain a conserved immunoreceptor tyrosine-based inhibitory motif (ITIM) that can potentially bind to Src-homology domain-containing phosphatases, such as SHP-1 and SHP-2 (1, 17). These are known to regulate functions of various cytokine receptors (18,19) and therefore raise the possibility that Siglec-8 not only functions as an inhibitory receptor, but also regulates other functions, including perhaps the IL-5 receptor. Direct validation of this hypothesis Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-5 Priming of Human Eosinophils Alters Siglec-8–Mediated Apoptosis Pathways

Nutku-Bilir¹,

Hudson²,

Bochner³

2008

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Previously, we have identified the sequential activation of reactive oxygen species (ROS), mitochondria, and caspase-3, -8, and -9, in Siglec-8-mediated eosinophil apoptosis. Cytokine priming, which normally prolongs eosinophil survival, paradoxically potentiated this proapoptotic effect. The mechanisms of Siglec-8-mediated apoptosis after priming were therefore explored. Using IL-5 as the priming stimulus, the rate of Siglec-8-induced eosinophil apoptosis was found to be enhanced compared with unprimed cells, and mechanisms differed after IL-5 priming in that neither a pan-caspase inhibitor, nor a specific caspase-3 inhibitor, could override apoptosis. IL-5 priming also accelerated Siglec-8-mediated dissipation of mitochondrial membrane potential. Finally, both the mitochondrial electron transport inhibitor rotenone, and the ROS inhibitors diphenyleneiodonium and antimycin, completely inhibited Siglec-8-mediated apoptosis, even after IL-5 priming. These data demonstrate that IL-5 priming enhances Siglec-8-mediated mitochondrial and ROS-dependent eosinophil apoptosis and eliminates caspase dependence. The potential clinical implication of these findings is that cytokine priming, as often occurs in vivo in asthma and other hypereosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent.Keywords: eosinophils; apoptosis; caspases; mitochondria; Siglec-8Siglec-8 is a member of the CD33 subfamily of the immunoglobulin gene superfamily of receptors (1). It is uniquely expressed on eosinophils, mast cells, and basophils (2). Although it exists as two splice variants, the consistent and predominant form contains two tyrosine-based cytoplasmic motifs implicated in cell signaling (3). Siglec-8 binds a unique carbohydrate structure, 69 sulfated sialyl-Lewis X (4). Engagement of Siglec-8 on blood eosinophils results in caspase-and mitochondria-dependent apoptosis (5). In addition, previous studies have shown that eosinophil survival-promoting cytokines, such as IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), fail to block apoptosis and instead enhance the sensitivity of eosinophils to undergo apoptosis in response to Siglec-8 engagement (6). In non-cytokine-primed eosinophils, Siglec-8 engagement induces activation of caspase-3, caspase-8, and caspase-9 (5). Based on experiments with pharmacologic inhibitors, caspases as well as mitochondria and reactive oxygen species (ROS) were identified as key constituents involved in Siglec-8-mediated apoptosis (5).Because cytokine priming occurs in vivo in a variety of allergic, parasitic, and other hypereosinophilic disorders (7), and because it enhances the pro-apoptotic effects of Siglec-8 engagement, the objective of the present studies was to identify the mechanisms of Siglec-8-mediated apoptosis after cytokine priming to determine how such treatment affects this apoptotic pathway. MATERIALS AND METHODS Antibodies, Reagents, and Recombinant ProteinsSiglec-8 immun...

show abstract

Section: Discussionmentioning

confidence: 99%

Interleukin-5 Priming of Human Eosinophils Alters Siglec-8–Mediated Apoptosis Pathways

Nutku-Bilir¹,

Hudson²,

Bochner³

2008

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…stimulating factor (GM-CSF), and triggering receptor expressed on myeloid cell-1 results in a decreased response in elderly individuals associated with altered signal transduction and changes in the structure, dynamics, and function of lipid raft-dependent signaling in these cells (28,107). Similarly, anti-apoptotic signals delivered by GM-CSF failed to rescue neutrophils from apoptosis in the elderly (29).…”

Section: Figure 2 Impaired Function Of Innate Immunity In Aged Indivmentioning

confidence: 99%

Aging of the Immune System as a Prognostic Factor for Human Longevity

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Response of neutrophils to GM-CSF has also been demonstrated to decline with age, resulting in an increase in apoptosis at the site of infection. This increased apoptosis of neutrophils observed in aged humans may account for the long-term persistence of inflammation in the elderly (100,216,373). The underlying basis for defects in neutrophil function in the elderly has been attributed either to modulation=s in cell membrane-mediated events or to defects in proximal signaling mechanisms, since stimulators such as phorbol esters are fully capable of inducing a relatively robust response in the elderly, primarily by overriding early receptor-mediated and membrane-associated activation events.…”

Section: Immune Senescence and Interventionsmentioning

confidence: 99%

Aging and Immune Function: Molecular Mechanisms to Interventions

Ponnappan

2011

Antioxidants & Redox Signaling

260

View full text Add to dashboard Cite

The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed ''immune senescence,'' manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFkB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551-1585.

show abstract

Age-related impairment of GM-CSF-induced signalling in neutrophils: Role of SHP-1 and SOCS proteins

Cited by 49 publications

References 104 publications

Interleukin-5 Priming of Human Eosinophils Alters Siglec-8–Mediated Apoptosis Pathways

Interleukin-5 Priming of Human Eosinophils Alters Siglec-8–Mediated Apoptosis Pathways

Aging of the Immune System as a Prognostic Factor for Human Longevity

Aging and Immune Function: Molecular Mechanisms to Interventions

Contact Info

Product

Resources

About