The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and...
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Autor*in:	Georg Gruenbacher [verfasserIn] Hubert Gander [verfasserIn] Andrea Rahm [verfasserIn] Gabriele Dobler [verfasserIn] Astrid Drasche [verfasserIn] Jakob Troppmair [verfasserIn] Walter Nussbaumer [verfasserIn] Martin Thurnher [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	P2Y11 ATP NAD+ IL-10 M2 macrophages

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 10(2019)
Übergeordnetes Werk:	volume:10 ; year:2019

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2019.01870

Katalog-ID:	DOAJ070952132

Internformat


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author_variant	g g gg h g hg a r ar g d gd a d ad j t jt w n wn m t mt
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allfields	10.3389/fimmu.2019.01870 doi (DE-627)DOAJ070952132 (DE-599)DOAJf7527065a0d64848875bd47014568c8c DE-627 ger DE-627 rakwb eng RC581-607 Georg Gruenbacher verfasserin aut The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy. P2Y11 ATP NAD+ IL-10 M2 macrophages Immunologic diseases. Allergy Hubert Gander verfasserin aut Andrea Rahm verfasserin aut Gabriele Dobler verfasserin aut Astrid Drasche verfasserin aut Jakob Troppmair verfasserin aut Walter Nussbaumer verfasserin aut Martin Thurnher verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.01870 kostenfrei https://doaj.org/article/f7527065a0d64848875bd47014568c8c kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
spelling	10.3389/fimmu.2019.01870 doi (DE-627)DOAJ070952132 (DE-599)DOAJf7527065a0d64848875bd47014568c8c DE-627 ger DE-627 rakwb eng RC581-607 Georg Gruenbacher verfasserin aut The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy. P2Y11 ATP NAD+ IL-10 M2 macrophages Immunologic diseases. Allergy Hubert Gander verfasserin aut Andrea Rahm verfasserin aut Gabriele Dobler verfasserin aut Astrid Drasche verfasserin aut Jakob Troppmair verfasserin aut Walter Nussbaumer verfasserin aut Martin Thurnher verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.01870 kostenfrei https://doaj.org/article/f7527065a0d64848875bd47014568c8c kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfields_unstemmed	10.3389/fimmu.2019.01870 doi (DE-627)DOAJ070952132 (DE-599)DOAJf7527065a0d64848875bd47014568c8c DE-627 ger DE-627 rakwb eng RC581-607 Georg Gruenbacher verfasserin aut The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy. P2Y11 ATP NAD+ IL-10 M2 macrophages Immunologic diseases. Allergy Hubert Gander verfasserin aut Andrea Rahm verfasserin aut Gabriele Dobler verfasserin aut Astrid Drasche verfasserin aut Jakob Troppmair verfasserin aut Walter Nussbaumer verfasserin aut Martin Thurnher verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.01870 kostenfrei https://doaj.org/article/f7527065a0d64848875bd47014568c8c kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsGer	10.3389/fimmu.2019.01870 doi (DE-627)DOAJ070952132 (DE-599)DOAJf7527065a0d64848875bd47014568c8c DE-627 ger DE-627 rakwb eng RC581-607 Georg Gruenbacher verfasserin aut The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy. P2Y11 ATP NAD+ IL-10 M2 macrophages Immunologic diseases. Allergy Hubert Gander verfasserin aut Andrea Rahm verfasserin aut Gabriele Dobler verfasserin aut Astrid Drasche verfasserin aut Jakob Troppmair verfasserin aut Walter Nussbaumer verfasserin aut Martin Thurnher verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.01870 kostenfrei https://doaj.org/article/f7527065a0d64848875bd47014568c8c kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsSound	10.3389/fimmu.2019.01870 doi (DE-627)DOAJ070952132 (DE-599)DOAJf7527065a0d64848875bd47014568c8c DE-627 ger DE-627 rakwb eng RC581-607 Georg Gruenbacher verfasserin aut The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy. P2Y11 ATP NAD+ IL-10 M2 macrophages Immunologic diseases. Allergy Hubert Gander verfasserin aut Andrea Rahm verfasserin aut Gabriele Dobler verfasserin aut Astrid Drasche verfasserin aut Jakob Troppmair verfasserin aut Walter Nussbaumer verfasserin aut Martin Thurnher verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.01870 kostenfrei https://doaj.org/article/f7527065a0d64848875bd47014568c8c kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
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authorswithroles_txt_mv	Georg Gruenbacher @@aut@@ Hubert Gander @@aut@@ Andrea Rahm @@aut@@ Gabriele Dobler @@aut@@ Astrid Drasche @@aut@@ Jakob Troppmair @@aut@@ Walter Nussbaumer @@aut@@ Martin Thurnher @@aut@@
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callnumber-first	R - Medicine
author	Georg Gruenbacher
spellingShingle	Georg Gruenbacher misc RC581-607 misc P2Y11 misc ATP misc NAD+ misc IL-10 misc M2 macrophages misc Immunologic diseases. Allergy The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation
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topic_title	RC581-607 The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation P2Y11 ATP NAD+ IL-10 M2 macrophages
topic	misc RC581-607 misc P2Y11 misc ATP misc NAD+ misc IL-10 misc M2 macrophages misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc P2Y11 misc ATP misc NAD+ misc IL-10 misc M2 macrophages misc Immunologic diseases. Allergy
topic_browse	misc RC581-607 misc P2Y11 misc ATP misc NAD+ misc IL-10 misc M2 macrophages misc Immunologic diseases. Allergy
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title	The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation
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title_full	The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation
author_sort	Georg Gruenbacher
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title_sort	human g protein-coupled atp receptor p2y11 is associated with il-10 driven macrophage differentiation
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title_auth	The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation
abstract	The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy.
abstractGer	The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy.
abstract_unstemmed	The G protein-coupled P2Y11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD+ has also been proposed to be a P2Y11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, which is under the control of AMPK, were also required for P2Y11 receptor expression. The P2Y11 receptor agonist ATPγS and NAD+ could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y11 receptor. Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
title_short	The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation
url	https://doi.org/10.3389/fimmu.2019.01870 https://doaj.org/article/f7527065a0d64848875bd47014568c8c https://www.frontiersin.org/article/10.3389/fimmu.2019.01870/full https://doaj.org/toc/1664-3224
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up_date	2024-07-03T17:37:29.707Z
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Both in a recombinant system and in macrophages, P2Y11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD+ signaling axis promotes P2Y11 receptor expression during M2 polarization of human macrophages in response to IL-10. 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The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

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