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A Comprehensive Data Mining Study Shows That Most Nuclear Receptors Wang et al. Journal of Hematology & Oncology (2017) 10:168 DOI 10.1186/s13045-017-0526-8 RESEARCH Open Access A comprehensive data mining study shows that most nuclear receptors act as newly proposed homeostasis-associated molecular pattern receptors Luqiao Wang1,2,6, Gayani Nanayakkara3, Qian Yang3,7, Hongmei Tan8, Charles Drummer3, Yu Sun2, Ying Shao3, Hangfei Fu2, Ramon Cueto2, Huimin Shan2, Teodoro Bottiglieri9, Ya-feng Li3, Candice Johnson3, William Y. Yang2, Fan Yang2, Yanjie Xu1, Hang Xi2, Weiqing Liu6, Jun Yu2,4, Eric T. Choi2,5, Xiaoshu Cheng1*, Hong Wang2,3 and Xiaofeng Yang2,3,4* Abstract Background: Nuclear receptors (NRs) can regulate gene expression; therefore, they are classified as transcription factors. Despite the extensive research carried out on NRs, still several issues including (1) the expression profile of NRs in human tissues, (2) how the NR expression is modulated during atherosclerosis and metabolic diseases, and (3) the overview of the role of NRs in inflammatory conditions are not fully understood. Methods: To determine whether and how the expression of NRs are regulated in physiological/pathological conditions, we took an experimental database analysis to determine expression of all 48 known NRs in 21 human and 17 murine tissues as well as in pathological conditions. Results: We made the following significant findings: (1) NRs are differentially expressed in tissues, which may be under regulation by oxygen sensors, angiogenesis pathway, stem cell master regulators, inflammasomes, and tissue hypo-/hypermethylation indexes; (2) NR sequence mutations are associated with increased risks for development of cancers and metabolic, cardiovascular, and autoimmune diseases; (3) NRs have less tendency to be upregulated than downregulated in cancers, and autoimmune and metabolic diseases, which may be regulated by inflammation pathways and mitochondrial energy enzymes; and (4) the innate immune sensor inflammasome/caspase-1 pathway regulates the expression of most NRs. Conclusions: Based on our findings, we propose a new paradigm that most nuclear receptors are anti-inflammatory homeostasis-associated molecular pattern receptors (HAMPRs). Our results have provided a novel insight on NRs as therapeutic targets in metabolic diseases, inflammations, and malignancies. Keywords: Nuclear receptors (NRs), Homeostasis-associated molecular pattern receptors, Atherosclerosis, Metabolic disease, Cardiovascular disease * Correspondence: [email protected]; [email protected] 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China 2Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Journal of Hematology & Oncology (2017) 10:168 Page 2 of 41 Background molecular patterns (HAMPs). Furthermore, we proposed Pathogen-associated molecular patterns (PAMPs) and that these HAMPs bind to their receptors (HAMP recep- danger-associated molecular patterns (DAMPs) generated tors) to initiate anti-inflammatory/homeostatic signaling during microbial invasion or tissue injury act as stimuli and promote inflammation resolution [5]. However, an and activate the innate immune system to respond to in- outstanding issue of whether endogenous lipophilic me- fection or injury [1]. The key cellular receptors that tabolites that bind to nuclear receptors can serve as recognize the “threat” signals initiated by PAMPs and HAMPs remains unknown. DAMPs are referred to as PRRs (pattern recognition re- The nuclear hormone receptor superfamily has 48 ceptors). One of the receptor families that are highly char- lipophilic ligand-activated receptors including 32 nuclear acterized as PRRs is the Toll-like receptor (TLR) family. hormone receptors (NHRs) for thyroid and steroid hor- Most of the TLRs are mainly located on the plasma mem- mones, retinoids, and vitamin D, as well as 16 orphan brane and activate inflammatory genes to counteract tis- nuclear receptors where the ligands are yet unknown sue injury and mediate repair. Moreover, TLRs work in [16–18]. Nuclear receptors (NRs), as transcription fac- synergy with cytosolic PRR families like NLRs (NOD (nu- tors, have the ability to directly bind to DNA and regu- cleotide-binding oligomerization domain)-like receptors) late the expression of adjacent genes [19, 20]. Ligands to recognize DAMPs, particularly in what we propose- for some of these NRs have been recently identified, in- d—inflammation-privileged tissues where inflammasome cluding lipid metabolites such as fatty acids, prostaglan- component genes that initiate inflammation are not con- dins, or cholesterol derivatives. These ligands can stitutively expressed [2, 3]. Additionally, four other PRR regulate gene expression by binding to NRs [21]. Ligand families including C-type lectin receptors, retinoid acid- binding to a NR results in a conformational change and inducible gene 1 (RIG-1), absent in melanoma-2 (AIM-2), activation of the receptor, leading to up- or downreg- and receptor for advanced glycation end products (RAGE, ulation of the target gene expression. Thus, NRs are also a receptor for high-mobility group box 1 (HMGB1)) involved in the regulation of various physiological have also been characterized [4]. processes including development, homeostasis, and Previously, using endogenous metabolite lysophospho- metabolism of the organism [22] and pathogenesis of lipids (LPLs) as a prototype, we proposed a new para- metabolic disease in response to metabolic/environ- digm for the first time that certain metabolites that play mental changes [23]. cellular functions during normal physiological status can However, despite the recent progress, there are many as- adapt as pro-inflammatory mediators at elevated con- pects of NRs that have not yet been explored: first, the ex- centrations. We named such metabolites as “conditional pression profile of NRs under physiological conditions in DAMPs” and their endogenous receptors as “conditional various human tissues have not been studied; second, DAMP receptors.” We further pointed out significant whether the expression of certain NRs are either upregu- loopholes in the current danger model which identify lated or downregulated in atherogenic and metabolic only the six receptors mentioned above as PRRs, which disease-related pathological conditions are not clear; third, we named as “classical DAMP receptors” [5]. Along the mechanistically, whether pro-/anti-inflammatory signaling line, we recently reported a series of significant findings is negatively/positively associated with the expression of on the expression and roles of caspase-1 in the NLR NRs is not known; and fourth, whether NRs have the cap- pathway in vascular inflammation [2, 6–15]. In the same acity to function as our newly proposed HAMP receptors, publication mentioned above, we concluded that activa- which suppress inflammatory responses and maintain tis- tion of inflammation by conditional DAMPs may be re- sue homeostasis in response to the stimulation of exogen- alized via binding to their own intrinsic receptors and ous and endogenous PAMPs/DAMPs. To address these may not necessarily always involve or “converge to” questions, we took a “panoramic view” at the tissue ex- TLRs, NLRs, and other classical DAMP receptors [5]. pression pattern of all 48 identified human and mouse Another significant problem associated with the current NRs. Our results demonstrated that NRs are differentially danger theory is that it fails to recognize the roles played expressed among tissues at physiological conditions, by potential endogenous metabolites in anti-inflammatory which may be regulated by oxygen sensors, vascular endo- responses, inflammation resolution, and maintenance of thelial growth factor pathways, stem cell master regula- homeostasis. Therefore, we further advanced the current tors, innate immune sensors, and DNA hypo-/ paradigm by proposing endogenous metabolites such as hypermethylation status. We also found that the lysophosphatidylserine and lysophosphatidylethanolamine expressions of certain NRs have less tendency to be upreg- that not only maintain homeostasis at physiological levels, ulated than to be downregulated in atherogenic condi- but also act as anti-inflammatory mediators to inhibit in- tions, metabolic diseases, which may be contributed by flammation and promote inflammation resolution at significant regulation of innate immune sensor caspase-1/ pathologically elevated levels as homeostasis-associated inflammasome pathway. Our findings provide novel Wang et al. Journal of Hematology & Oncology (2017) 10:168 Page 3 of 41 insights into the upstream regulation of nuclear receptors NR genes in 21 different human and 17 mouse tissues in- in physiological, autoimmune arthritis, and cardiovascular cluding
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