Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression

Núñez, Vanessa; Alameda, Daniel; Rico, Daniel; Mota, Rubén; Gonzalo, Pilar; Cedenilla, Marta; Fischer, Thierry; Boscá, Lisardo; Glass, Christopher K.; Arroyo, Alicia G.; Ricote, Mercedes

doi:10.1073/pnas.0913545107

Cited by 116 publications

(90 citation statements)

References 42 publications

(53 reference statements)

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“…All-trans retinoic acid, through activation of RAR, suppresses the downregulation of MAFB during osteoclast differentiation (48). However, in agreehowever, very little is known about their in vivo functions (8,29). Our analysis demonstrates that the role of RXR signaling in osteoclastogenesis under basal physiological conditions is independent of RXR heterodimeric partners with known roles in bone physiology (40)(41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 74%

“…In a transfection assay in the LXR-, PPAR-, and RXRdeficient cell line RAW264.7 (ref. 29 and Supplemental Figure 9, A and B), the activity of a 1.5-kilobase Mafb promoter was upregulated by LG268 and 9cRA and downregulated by LG754 only in the presence of overexpressed RXRα ( Figure 6D). Moreover, LG754 inhibited 9cRA-induced Mafb promoter activation (Supplemental Figure 9C).…”

Section: Rxrs Regulate Osteoclastogenesis In Vivomentioning

confidence: 98%

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Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Menéndez-Gutierrez¹,

Röszer²,

Fuentes³

et al. 2015

J. Clin. Invest.

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R e s e a R c h a R t i c l e8under this pathological condition, we induced estrogen deficiency by bilateral ovariectomy (OvX) in 20-week-old WT and RXR-KO mice and assessed bone loss over a further 8 weeks. Consistent with the lack of a skeletal phenotype in RXR-KO females (Supplemental Figure 3), age-and sex-matched sham-operated WT and RXR-KO mice showed no differences in bone architecture or osteoclast activity ( Figure 2). However, after OvX, loss of trabecular bone mass was significantly lower in RXR-KO mice (Figure 2, A-D). In WT mice, OvX led to a marked increase in osteoclast activity, shown by a rise in urine DPD and plasma CTX concentrations (Figure 2, E and F). In contrast, the increase in DPD and CTX concentrations was significantly lower in ovariectomized RXR-KO mice (Figure 2, E and F). These findings indicate that the diminished osteoclast activity in RXR-KO female mice makes them less prone to bone loss upon OvX. Lack of RXRs leads to formation of giant and nonresorbing osteoclasts in vitro.To determine the mechanism underlying the abnormal osteoclast activation in RXR-KO mice, we cultured bone marrow cells in the presence of the cytokines macrophage colony-stimulating factor (M-CSF) and RANKL (16). Osteoclasts differentiated from RXR-KO bone marrow were significantly larger than WT-derived osteoclasts and contained more nuclei (Figure 3, A-C). In contrast, osteoclast differentiation from bone marrow cells lacking RXRα but not RXRβ was normal, supporting the functional redundancy of RXRα and RXRβ in hematopoietic cells (Supplemental Figure 5). Enlargement of osteoclasts can result in increased bone resorption (17); however, the abnormally large RXR-KO osteoclasts displayed low lytic activity when cultured in calcium-phosphate-coated plates (Figure 3D) or on bovine cortical bone slices ( Figure 3E). RXR-KO osteoclasts also showed low expression of Acp5, matrix metallopeptidase 9 (Mmp9), cathepsin-K (CtsK), and Car2, which encode molecules crucial for extracellular matrix degradation and bone resorption ( Figure 3F). In addition, real-time imaging showed that RXR-KO osteoclasts had an increased spreading over the substrate compared with WT osteoclasts ( Figure 3G and Supplemental Video 1). These in vitro results are consistent with our in vivo observations, indicating that the lack of RXRs in osteoclast progenitors leads to a cell-autonomous effect on osteoclast differentiation and activation.The M-CSF response is altered in RXR-KO osteoclast progenitors. Osteoclast size is determined by the response of osteoclast progenitors to M-CSF, which controls their proliferation and survival (18,19). This cytokine also stimulates activities of the mature resorptive osteoclast, such as spreading, motility, and cytoskeletal organization (20). We thus hypothesized that the RXR-KO osteoclast phenotype could be due to an altered M-CSF response. To test this, we first characterized the capacity of osteoclast progenitors to form myeloid colony-forming units (CFUs) and to divide in response to M-CSF. After 12 days...

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Section: Discussionmentioning

confidence: 74%

Section: Rxrs Regulate Osteoclastogenesis In Vivomentioning

confidence: 98%

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Menéndez-Gutierrez¹,

Röszer²,

Fuentes³

et al. 2015

J. Clin. Invest.

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“…The retinoid X receptors (RXR) were identified in 1990 as orphan receptors that exhibited diverse transcriptional responses (20). RXRs play a vital role in the nuclear receptor superfamily, forming heterodimers with many other family members; as a result, RXRs are implicated in the control of various physiologic processes (21). RXRA is a member of the RXR family that can be activated by sterol (22).…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA HULC Modulates Abnormal Lipid Metabolism in Hepatoma Cells through an miR-9–Mediated RXRA Signaling Pathway

et al. 2015

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HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling. Cancer Res; 75(5); 846-57. Ó2015 AACR.

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“…In addition to the well-known immunosuppressive effects of glucocorticoids, many studies have revealed that physiological levels of glucocorticoids actually enhance the immune and inflammatory response (Galon et al, 2002;Shuto et al, 2002;Goulding, 2004;Hermoso et al, 2004;Sakai et al, 2004;Dhabhar, 2009;Busillo et al, 2011). Several other nuclear hormone receptors, including estrogen receptors (ERs), peroxisome proliferatoractivated receptors (PPARs), vitamin D receptors (VDRs), retinoid-related orphan receptors (RORs), retinoid X receptors (RXRs) and liver X receptors (LXRs), have also been found to positively regulate innate immunity and proinflammatory cytokine expression (Tontonoz et al, 1998;Hong and Tontonoz, 2008;Jetten, 2009;Baeke et al, 2010;Nunez et al, 2010). All together, these reports exemplify the complex and sometimes contradictory regulation of innate immune and inflammatory responses by steroid/retinoid hormones and their receptors; therefore a more simple and genetically tractable system for studying the interface between steroids and innate immunity would be highly valuable.…”

Section: Introductionmentioning

confidence: 99%

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

Rus

Flatt

Tong

et al. 2013

EMBO J

131

145

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Throughout the animal kingdom, steroid hormones have been implicated in the defense against microbial infection, but how these systemic signals control immunity is unclear. Here, we show that the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial infection. We identify a group of steroid-regulated transcription factors as well as two GATA transcription factors that act as repressors and activators of the immune response and are required for the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that Drosophila use complex mechanisms to modulate innate immune responses, and identify a transcriptional hierarchy that integrates steroid signalling and immunity in animals.

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Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression

Cited by 116 publications

References 42 publications

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling

Long Noncoding RNA HULC Modulates Abnormal Lipid Metabolism in Hepatoma Cells through an miR-9–Mediated RXRA Signaling Pathway

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

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