Liver X receptor nuclear receptors are transcriptional regulators of dendritic cell chemotaxis

Susana Beceiro, Attila Pap, Zsolt Czimmerer, Tamer Sallam, Jose A. Guillén, Germán Gallardo, Cynthia Hong, Noelia A-Gonzalez, Carlos Tabraue, Mercedes Diaz, Felix Lopez, Jonathan Matalong, Annabel F. Valledor, Pilar Dominguez, Carlos Ardavin, Cristina Delgado-Martin, Santiago Partida-Sanchez, Jose Luis Rodriguez-Fernandez, Laszlo Nagy, Peter TontonoAntonio Castrillo

Research output: Contribution to journalArticle

Abstract

The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR-/-) LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.

Original languageEnglish (US)
Article numbere00534
JournalMolecular and Cellular Biology
Volume38
Issue number10
DOIs
StatePublished - May 1 2018
Externally publishedYes

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Chemotaxis
Cytoplasmic and Nuclear Receptors
Dendritic Cells
LDL Receptors
Myeloid Cells
Atherosclerosis
Leukocytes
Inflammation
Lipids
Liver X Receptors
Emigration and Immigration
Homeostasis
Macrophages
Maintenance
Pharmacology
Ligands

Keywords

  • CD38
  • Chemotaxis
  • Dendritic cells
  • Inflammation
  • Liver X receptor
  • Macrophages
  • Migration
  • Nuclear receptors
  • Regulation of gene expression
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Beceiro, S., Pap, A., Czimmerer, Z., Sallam, T., Guillén, J. A., Gallardo, G., ... Castrillo, A. (2018). Liver X receptor nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. Molecular and Cellular Biology, 38(10), [e00534]. https://doi.org/10.1128/MCB.00534-17

Liver X receptor nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. / Beceiro, Susana; Pap, Attila; Czimmerer, Zsolt; Sallam, Tamer; Guillén, Jose A.; Gallardo, Germán; Hong, Cynthia; A-Gonzalez, Noelia; Tabraue, Carlos; Diaz, Mercedes; Lopez, Felix; Matalong, Jonathan; Valledor, Annabel F.; Dominguez, Pilar; Ardavin, Carlos; Delgado-Martin, Cristina; Partida-Sanchez, Santiago; Rodriguez-Fernandez, Jose Luis; Nagy, Laszlo; Tontono, Peter; Castrillo, Antonio.

In: Molecular and Cellular Biology, Vol. 38, No. 10, e00534, 01.05.2018.

Research output: Contribution to journalArticle

Beceiro, S, Pap, A, Czimmerer, Z, Sallam, T, Guillén, JA, Gallardo, G, Hong, C, A-Gonzalez, N, Tabraue, C, Diaz, M, Lopez, F, Matalong, J, Valledor, AF, Dominguez, P, Ardavin, C, Delgado-Martin, C, Partida-Sanchez, S, Rodriguez-Fernandez, JL, Nagy, L, Tontono, P & Castrillo, A 2018, 'Liver X receptor nuclear receptors are transcriptional regulators of dendritic cell chemotaxis', Molecular and Cellular Biology, vol. 38, no. 10, e00534. https://doi.org/10.1128/MCB.00534-17
Beceiro, Susana ; Pap, Attila ; Czimmerer, Zsolt ; Sallam, Tamer ; Guillén, Jose A. ; Gallardo, Germán ; Hong, Cynthia ; A-Gonzalez, Noelia ; Tabraue, Carlos ; Diaz, Mercedes ; Lopez, Felix ; Matalong, Jonathan ; Valledor, Annabel F. ; Dominguez, Pilar ; Ardavin, Carlos ; Delgado-Martin, Cristina ; Partida-Sanchez, Santiago ; Rodriguez-Fernandez, Jose Luis ; Nagy, Laszlo ; Tontono, Peter ; Castrillo, Antonio. / Liver X receptor nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. In: Molecular and Cellular Biology. 2018 ; Vol. 38, No. 10.
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AU - Pap, Attila

AU - Czimmerer, Zsolt

AU - Sallam, Tamer

AU - Guillén, Jose A.

AU - Gallardo, Germán

AU - Hong, Cynthia

AU - A-Gonzalez, Noelia

AU - Tabraue, Carlos

AU - Diaz, Mercedes

AU - Lopez, Felix

AU - Matalong, Jonathan

AU - Valledor, Annabel F.

AU - Dominguez, Pilar

AU - Ardavin, Carlos

AU - Delgado-Martin, Cristina

AU - Partida-Sanchez, Santiago

AU - Rodriguez-Fernandez, Jose Luis

AU - Nagy, Laszlo

AU - Tontono, Peter

AU - Castrillo, Antonio

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N2 - The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR-/-) LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.

AB - The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DCs), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished the LXR-dependent induction of DC chemotaxis. Using the low-density lipoprotein receptor-deficient (LDLR-/-) LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for the efficient emigration of DCs in response to chemotactic signals during inflammation.

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