scholarly journals Innate Immune Modulation by GM-CSF and IL-3 in Health and Disease

2019 ◽  
Vol 20 (4) ◽  
pp. 834 ◽  
Author(s):  
Francesco Borriello ◽  
Maria Galdiero ◽  
Gilda Varricchi ◽  
Stefania Loffredo ◽  
Giuseppe Spadaro ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Experimental Models ◽  
Innate Immune ◽  
Immune Effector ◽  
Gm Csf ◽  
Innate Immune Effector ◽  
Macrophage Colony ◽  
Emergency Myelopoiesis

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies.

scholarly journals Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lúcia Moreira-Teixeira ◽  
Philippa J. Stimpson ◽  
Evangelos Stavropoulos ◽  
Sabelo Hadebe ◽  
Probir Chakravarty ◽  
...  
Keyword(s):  
Disease Severity ◽  
Innate Immune ◽  
Neutrophil Extracellular Trap ◽  
Type I ◽  
Type I Ifn ◽  
Immune Effector ◽  
Gm Csf ◽  
Innate Immune Effector ◽  
Important Cytokine

Abstract Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.

scholarly journals Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

2014 ◽  
Vol 82 (10) ◽  
pp. 4405-4413 ◽  
Author(s):  
Sarah E. Davis ◽  
Alex Hopke ◽  
Steven C. Minkin ◽  
Anthony E. Montedonico ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
De Novo ◽  
Invasive Disease ◽  
Innate Immune ◽  
Dependent Manner ◽  
Content Type ◽  
Immune Effector ◽  
Host Interactions ◽  
Innate Immune Effector

ABSTRACTThe virulence ofCandida albicansin a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase geneCHO1(i.e.,cho1Δ/Δ) eliminates PS and blocks thede novopathway for PE biosynthesis. In addition, thecho1Δ/Δ mutant's ability to cause invasive disease is severely compromised. Thecho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-typeC. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. Thecho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS inC. albicansresults in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.

scholarly journals Neutrophil Extracellular Traps Serve as Key Effector Molecules in the Protection Against Phialophora verrucosa

2021 ◽  
Vol 186 (3) ◽  
pp. 367-375
Author(s):  
Qin Liu ◽  
Wenjuan Yi ◽  
Si Jiang ◽  
Jiquan Song ◽  
Pin Liang
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Immune Effector ◽  
Phialophora Verrucosa ◽  
Extracellular Traps ◽  
Sytox Green ◽  
Innate Immune Effector ◽  
Pathogen Control ◽  
Extracellular Structures

AbstractPhialophora verrucosa (P. verrucosa) is a pathogen that can cause chromoblastomycosis and phaeohyphomycosis. Recent evidence suggests that neutrophils can produce neutrophil extracellular traps (NETs) that can protect against invasive pathogens. As such, we herein explored the in vitro functional importance of P. verrucosa-induced NET formation. By assessing the co-localization of neutrophil elastase and DNA, we were able to confirm the formation of classical NETs entrapping P. verrucosa specimens. Sytox Green was then used to stain these NETs following neutrophil infection with P. verrucosa in order to quantify the formation of these extracellular structures. NET formation was induced upon neutrophil exposure to both live, UV-inactivated, and dead P. verrucosa fungi. The ability of these NETs to kill fungal hyphae and conidia was demonstrated through MTT and pouring plate assays, respectively. Overall, our results confirmed that P. verrucosa was able to trigger the production of NETs, suggesting that these extracellular structures may represent an important innate immune effector mechanism controlling physiological responses to P. verrucosa infection, thereby aiding in pathogen control during the acute phases of infection.

scholarly journals Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia

2018 ◽  
Vol 9 (11) ◽  
pp. e208 ◽  
Author(s):  
Janette Furuzawa-Carballeda ◽  
Lise Boon ◽  
Gonzalo Torres-Villalobos ◽  
Fernanda Romero-Hernández ◽  
Estefania Ugarte-Berzal ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 9 ◽  
Innate Immune ◽  
Gelatinase B ◽  
Immune Effector ◽  
Effector Molecule ◽  
Innate Immune Effector ◽  
Metalloproteinase 9

scholarly journals Actin polymerization as a key innate immune effector mechanism to controlSalmonellainfection

2014 ◽  
Vol 111 (49) ◽  
pp. 17588-17593 ◽  
Author(s):  
Si Ming Man ◽  
Andrew Ekpenyong ◽  
Panagiotis Tourlomousis ◽  
Sarra Achouri ◽  
Eugenia Cammarota ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Innate Immune ◽  
Immune Effector ◽  
Effector Mechanism ◽  
Innate Immune Effector

scholarly journals The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway

2020 ◽  
Vol 17 (11) ◽  
pp. 1163-1179
Author(s):  
Rilin Deng ◽  
Chaohui Zuo ◽  
Yongqi Li ◽  
Binbin Xue ◽  
Zhen Xun ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Innate Immune ◽  
Immune Effector ◽  
Cancer Immunity ◽  
Innate Immune Effector ◽  
Canonical Wnt

scholarly journals GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress

2006 ◽  
Vol 291 (6) ◽  
pp. L1246-L1255 ◽  
Author(s):  
Carlos E. O. Baleeiro ◽  
Paul J. Christensen ◽  
Susan B. Morris ◽  
Michael P. Mendez ◽  
Steven E. Wilcoxen ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cell ◽  
Innate Immune Response ◽  
Alveolar Epithelial Cell ◽  
Critical Role ◽  
Innate Immune ◽  
Alveolar Epithelial Cells ◽  
Bacterial Colony ◽  
Alveolar Epithelial ◽  
Gm Csf

We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.

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