Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

Bartosz Pilecki; Helle Wulf-Johansson; Christian Støttrup; Patricia Troest Jørgensen; Pascal Djiadeu; Anders Bathum Nexøe; Anders Schlosser; Søren Werner Karlskov Hansen; Jens Madsen; Howard William Clark; Claus Henrik Nielsen; Jørgen Vestbo; Nades Palaniyar; Uffe Holmskov; Grith Lykke Sorensen

doi:10.3389/fimmu.2018.03013

Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

Bartosz Pilecki, Helle Wulf-Johansson, Christian Støttrup, Patricia Troest Jørgensen, Pascal Djiadeu, Anders Bathum Nexøe, Anders Schlosser, Søren Werner Karlskov Hansen, Jens Madsen, Howard William Clark, Claus Henrik Nielsen, Jørgen Vestbo, Nades Palaniyar, Uffe Holmskov, Grith Lykke Sorensen

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Abstract

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

Originalsprog	Engelsk
Artikelnummer	3013
Tidsskrift	Frontiers in Immunology
Vol/bind	9
Antal sider	12
ISSN	1664-3224
DOI	https://doi.org/10.3389/fimmu.2018.03013
Status	Udgivet - 18 dec. 2018

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10.3389/fimmu.2018.03013Licens: CC BY

Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide SynthesisForlagets udgivne version, 1,98 MBLicens: CC BY

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Pilecki, B., Wulf-Johansson, H., Støttrup, C., Jørgensen, P. T., Djiadeu, P., Nexøe, A. B., Schlosser, A., Hansen, S. W. K., Madsen, J., Clark, H. W., Nielsen, C. H., Vestbo, J., Palaniyar, N., Holmskov, U., & Sorensen, G. L. (2018). Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis. Frontiers in Immunology, 9, Artikel 3013. https://doi.org/10.3389/fimmu.2018.03013

Pilecki, B, Wulf-Johansson, H, Støttrup, C, Jørgensen, PT, Djiadeu, P, Nexøe, AB, Schlosser, A, Hansen, SWK, Madsen, J, Clark, HW, Nielsen, CH, Vestbo, J, Palaniyar, N, Holmskov, U & Sorensen, GL 2018, 'Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis', Frontiers in Immunology, bind 9, 3013. https://doi.org/10.3389/fimmu.2018.03013

@article{0461b73c14f746b78500d2fc79d4e0bf,

title = "Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis",

abstract = "Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.",

keywords = "ceramide, ceramide synthase, cigarette smoke (CS), mouse models, surfactant protein D (SP-D)",

author = "Bartosz Pilecki and Helle Wulf-Johansson and Christian St{\o}ttrup and J{\o}rgensen, {Patricia Troest} and Pascal Djiadeu and Nex{\o}e, {Anders Bathum} and Anders Schlosser and Hansen, {S{\o}ren Werner Karlskov} and Jens Madsen and Clark, {Howard William} and Nielsen, {Claus Henrik} and J{\o}rgen Vestbo and Nades Palaniyar and Uffe Holmskov and Sorensen, {Grith Lykke}",

year = "2018",

month = dec,

day = "18",

doi = "10.3389/fimmu.2018.03013",

language = "English",

volume = "9",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

AU - Pilecki, Bartosz

AU - Wulf-Johansson, Helle

AU - Støttrup, Christian

AU - Jørgensen, Patricia Troest

AU - Djiadeu, Pascal

AU - Nexøe, Anders Bathum

AU - Schlosser, Anders

AU - Hansen, Søren Werner Karlskov

AU - Madsen, Jens

AU - Clark, Howard William

AU - Nielsen, Claus Henrik

AU - Vestbo, Jørgen

AU - Palaniyar, Nades

AU - Holmskov, Uffe

AU - Sorensen, Grith Lykke

PY - 2018/12/18

Y1 - 2018/12/18

N2 - Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

AB - Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

KW - ceramide

KW - ceramide synthase

KW - cigarette smoke (CS)

KW - mouse models

KW - surfactant protein D (SP-D)

U2 - 10.3389/fimmu.2018.03013

DO - 10.3389/fimmu.2018.03013

M3 - Journal article

C2 - 30619359

SN - 1664-3224

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 3013

ER -

Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

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