Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia

Sinead A. O'Sullivan; Catherine O’Sullivan; Luke M. Healy; Kumlesh K. Dev; Graham Sheridan

doi:10.1111/jnc.14313

Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia

Sinead A. O'Sullivan, Catherine O’Sullivan, Luke M. Healy, Kumlesh K. Dev, Graham Sheridan

Research output: Contribution to journal › Article › peer-review

Abstract

Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R – S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In the current study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX lipopolysaccharide-induced CXC chemokine), expression were quantified. Results showed pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, 1) CXCL5/LIX, 2) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10), and 3) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase (SphK) attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

Original language	English
Pages (from-to)	736-747
Journal	Journal of Neurochemistry
Volume	144
Issue number	6
DOIs	https://doi.org/10.1111/jnc.14313
Publication status	Published - 27 Jan 2018

Bibliographical note

This is the peer reviewed version of the following article: Sinead A. O'Sullivan, Catherine O'Sullivan, Luke M. Healy, Kumlesh K. Dev and Graham K. Sheridan, Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia, Journal of Neurochemistry, 2018, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jnc.14313/full. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Keywords

Astrocyte
Chemokine
CXCL5
FTY720
Microglia
Sphingosine 1-phosphate
Toll- like receptor 4

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Cite this

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title = "Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia",

abstract = "Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R – S1P5R. The drug Gilenya{\textregistered} (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In the current study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX lipopolysaccharide-induced CXC chemokine), expression were quantified. Results showed pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, 1) CXCL5/LIX, 2) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10), and 3) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase (SphK) attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.",

keywords = "Astrocyte, Chemokine, CXCL5, FTY720, Microglia, Sphingosine 1-phosphate, Toll- like receptor 4",

author = "O'Sullivan, {Sinead A.} and Catherine O{\textquoteright}Sullivan and Healy, {Luke M.} and Dev, {Kumlesh K.} and Graham Sheridan",

note = "This is the peer reviewed version of the following article: Sinead A. O'Sullivan, Catherine O'Sullivan, Luke M. Healy, Kumlesh K. Dev and Graham K. Sheridan, Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia, Journal of Neurochemistry, 2018, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jnc.14313/full. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.",

year = "2018",

month = jan,

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doi = "10.1111/jnc.14313",

language = "English",

volume = "144",

pages = "736--747",

journal = "Journal of Neurochemistry",

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T1 - Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia

AU - O'Sullivan, Sinead A.

AU - O’Sullivan, Catherine

AU - Healy, Luke M.

AU - Dev, Kumlesh K.

AU - Sheridan, Graham

N1 - This is the peer reviewed version of the following article: Sinead A. O'Sullivan, Catherine O'Sullivan, Luke M. Healy, Kumlesh K. Dev and Graham K. Sheridan, Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia, Journal of Neurochemistry, 2018, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jnc.14313/full. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

PY - 2018/1/27

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N2 - Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R – S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In the current study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX lipopolysaccharide-induced CXC chemokine), expression were quantified. Results showed pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, 1) CXCL5/LIX, 2) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10), and 3) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase (SphK) attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

AB - Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R – S1P5R. The drug Gilenya® (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalisation and functional antagonism. Internalisation of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In the current study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX lipopolysaccharide-induced CXC chemokine), expression were quantified. Results showed pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, 1) CXCL5/LIX, 2) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10), and 3) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase (SphK) attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

KW - Astrocyte

KW - Chemokine

KW - CXCL5

KW - FTY720

KW - Microglia

KW - Sphingosine 1-phosphate

KW - Toll- like receptor 4

U2 - 10.1111/jnc.14313

DO - 10.1111/jnc.14313

M3 - Article

SN - 0022-3042

VL - 144

SP - 736

EP - 747

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

IS - 6

ER -

Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia

Abstract

Bibliographical note

Keywords

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