Granulocyte-Macrophage Colony Stimulating Factor Exerts Protective and Immunomodulatory Effects in Cortical Trauma

Kelso, Matthew L.; Elliott, Bret R.; Haverland, Nicole A.; Mosley, R. Lee; Gendelman, Howard Eliot

doi:10.1016/j.jneuroim.2014.11.002

Cited by 32 publications

(29 citation statements)

References 55 publications

(79 reference statements)

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“…The immediate increase in TNFα, IL1α, IL1β, and IL18 could induce the increases in chemotactic factors for immune cells (MCP1, G-CSF, GM-CSF, MIP3α, and RANTES) detected post pFUS+MB (33,62,66,67). Although these chemotactic factors are associated with injury or inflammation, the increased expression of MIP, RANTES, and GM-CSF also may contribute to the closure of the BBB, thereby protecting the brain from further neuronal injury (9,48,66,68). The increased expression of antiinflammatory cytokines (IL4, IL10, and IL13) following pFUS+MB could limit the extent of injury, promote neuronal survival, and induce microglial apoptosis (69)(70)(71)(72).…”

Section: Discussionmentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

349

388

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MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

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Section: Discussionmentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

349

388

View full text Add to dashboard Cite

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“…GM-CSF, nervous system, and pain GM-CSF has neuroprotective effects in models of neurological diseases and injury which have been proposed to be a result of direct action of GM-CSF on neurons (Schäbitz et al, 2008;Kelso et al, 2015). GM-CSFR has been reported to be expressed on neurons (Schweizerhof et al, 2009;Stösser et al, 2011;Ridwan et al, 2012;Bali et al, 2013) and to sensitize nerves to mechanical stimuli via a direct action on neurons (Schweizerhof et al, 2009;Zhang et al, 2019).…”

Section: Neutrophils and Eosinophilsmentioning

confidence: 99%

GM-CSF in inflammation

Hamilton

2019

Journal of Experimental Medicine

202

189

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Granulocyte–macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.

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“…10 GM-CSF is neuroprotective after a wide range of neurotrauma, exerting neuroprotective effects by diminishing expression of apoptosis-related genes. [11][12][13][14][15] …”

Section: Normal Brain Tissue Synthesizes G(m)-csfmentioning

confidence: 99%

“…[56][57][58] Lymphopenia in GB, relative or absolute, negatively affects prognosis and success of both current standard treatment of GB with temozolomide plus radiation. 59,60 In mice subjected to controlled cortical impact, Kelso et al 15 showed that treatment with GM-CSF increased CD4 + CD25 + regulatory T-cell (Treg) numbers in cervical lymph nodes coincident with decreased CNS lesion volumes and increased cortical tissue sparing. Transcriptomic analysis showed that GM-CSF induces robust immune inhibitory and neuroprotective responses 7 days following controlled cortical impact.…”

Section: Elevated G(m)-csf Is Immunosuppressive In Gbmentioning

confidence: 99%

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Kast¹,

Hill

Wion

et al. 2017

Tumour Biol.

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Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration-and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

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Granulocyte-Macrophage Colony Stimulating Factor Exerts Protective and Immunomodulatory Effects in Cortical Trauma

Cited by 32 publications

References 55 publications

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

GM-CSF in inflammation

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

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