Hypoxia-inducible factor 1 in autoimmune diseases

Hypoxia-inducible factor 1 in autoimmune diseases

Cellular Immunology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm...

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Cellular Immunology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm

Review article

Hypoxia-inducible factor 1 in autoimmune diseases Wei Deng, Xuebing Feng, Xia Li, Dandan Wang, Lingyun Sun ⇑ Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, PR China

a r t i c l e

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Article history: Received 27 July 2015 Revised 6 April 2016 Accepted 6 April 2016 Available online xxxx Keywords: HIF-1 Inflammation Neovascularization Immune responses Fibrosis Metabolism

a b s t r a c t Autoimmune disorders are a complicated and varied group of diseases arising from inappropriate immune responses. Recent studies have demonstrated that ongoing inflammatory and immune responses are associated with increased oxygen consumption, a process resulting in localized tissue hypoxia within inflammatory lesions (‘‘inflammatory hypoxia”), in which hypoxia-inducible factor 1 (HIF-1), an oxygen-sensitive transcription factor that allows adaptation to hypoxia environments, has been shown to play an important function. HIF-1 is a regulator of angiogenesis and immune system. Besides, HIF-1-mediated metabolic shift and fibrosis may also play crucial roles in some autoimmune disorders. Firstly, we briefly summarize the role of HIF-1 in angiogenesis, immune responses and fibrosis. Secondly, we will show the major recent findings demonstrating a role for HIF-1 signaling in autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, systemic sclerosis and multiple sclerosis. The growing evidences may prompt HIF-1 to be a new target for treatment of autoimmune diseases. Ó 2016 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cellular consequences of high-level HIF-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. HIF-1 and angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. HIF-1 and immune responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. HIF-1 and fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HIF-1 in autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. HIF-1 in RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. HIF-1 in IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. HIF-1 in psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. HIF-1 in SSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. HIF-1 in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hypoxia-inducible factor 1 (HIF-1), the oxygen-sensitive transcription factor that allows adaptation to hypoxia environments, is a heterodimer of one oxygen-regulated a- and one constitutively ⇑ Corresponding author.

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expressed b-subunit [1]. Each subunit contains basic helix-loophelix-PAS (bHLH-PAS) domains that mediate heterodimerization and DNA hypoxia response elements (HREs) binding [2,3]. Because HIF-1b is excessive in vivo, HIF-1 transcriptional activity is mainly determined by HIF-1a protein levels [4]. Besides HIF-1, the family of hypoxia-inducible factors has two other isotypes, HIF-2 and HIF3, which also play roles in transcriptional responses to hypoxia, immune systems, neovascularization et al. [5–7]. However, HIF-1

E-mail address: [email protected] (L. Sun). http://dx.doi.org/10.1016/j.cellimm.2016.04.001 0008-8749/Ó 2016 Elsevier Inc. All rights reserved.

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is one of the most important hypoxia-inducible factors involved in cellular metabolism, tissue repair, and inflammatory [8–13]. In normoxia, HIF-1a is rapidly hydroxylated and degraded in Von Hippel-Lindau tumor suppressor protein (VHL)-mediated proteasomal pattern by the prolyl hydroxylase domaincontaining protein (PHD). PHD takes O2 as a substrate, therefore, under hypoxic conditions its activity is declined. Factor inhibiting HIF-1 (FIH-1) could also suppress HIF-1a transcriptional activity under normoxia. By using O2 and a-ketoglutarate as substrates, it hydroxylates an asparaginyl residue on HIF-1a and then prevents the association of HIF-1a with the p300 coactivator protein [14]. Under hypoxic environment, both PHD and FIH1 activities are inhibited. Consequently, the a-subunit heterodimerises with the b-subunit to formulate HIF-1 and promote the transcriptional activities of target genes by binding to the HREs [13,15–17]. Studies have demonstrated that ongoing inflammatory and immune responses are associated with increased oxygen consumption, a process resulting in localized tissue hypoxia within inflammatory lesions (‘‘inflammatory hypoxia”) [18,19]. Conditional knockout of HIF-1 in specific types of cells has indicated vital roles of this factor in B lymphocyte development (using lymphocytes specific-HIF-1a-knockout mice) [20], T lymphocyte differentiation (in HIF-1a-knockout T cells) [8,21], and innate immune response (in both HIF-1a-deficient macrophages and dendritic cells) [22]. Recently it has been reported that HIF-1 contributes to the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, systemic sclerosis (SSc) and multiple sclerosis (MS) [23–27]. In this review we update the recent findings on the role of HIF-1 in the autoimmune diseases.

2. Cellular consequences of high-level HIF-1 2.1. HIF-1 and angiogenesis In both physiological and pathological states, neovascularization is usually connected with hypoxia or ‘‘inflammatory hypoxia” [28,29]. HIF-1, as one of the most important product of hypoxia, is believed to orchestrate the process of angiogenesis. Current studies have shown that HIF-1 may contribute to angiogenesis from 3 aspects: 1) activating several angiogenic genes and their receptors (VEGF, vascular endothelial growth factor; PlGF, placental growth factor; PDGFB, platelet-derived growth factor-b et al.); 2) regulating proangiogenic chemokines and receptors (SDF-1a, stromal cell derived factor 1a, and S1P, sphingosine-1-phosphate, and receptors CXCR4, C-X-C chemokine receptor type 4, and S1PRs, sphingosine-1-phosphate receptors) to recruit endothelial progenitor cells; 3) enhancing endothelial cells proliferation and division (regulating cyclins, Wnt signaling, et al.) [29,30]. Among them, VEGF is a master of HIF-1-mediated angiogenesis. It has been reported that benzo[a]pyrene opposes angiogenesis because of the inhibitory effect of the metabolite benzo[a]pyrene-3,6-dione on VEGF expression through HIF-1-binding site [31] (Fig. 1). Hypoxia or ‘‘inflammatory hypoxia” usually enhanced in pathological states such as solid tumors or chronic inflammatory disorders [28,32]. Taken the pathological conditions into account, angiogenesis here may be different from that in physiological states. In tumor cells, accumulated HIF-1 promotes TAp73 and DNp73 (two major forms of p73) stabilization. Thus, TAp73 and DNp73 can up-regulate pro-angiogenic genes such as VEGF-A, PDGFB et al. to support angiogenesis and tumorigenesis [33,34]. Besides, HIF-1’s transcriptional activity can also be increased by other proteins such

Fig. 1. The model of hypoxia-inducible factor 1-mediated angiogenesis. In physiological states, HIF-1 is usually stimulated by hypoxia directly and indirectly. While in pathological states, HIF-1 can be stimulated by hypoxia, inflammatory cytokines (e.g. TNF-a, IL-1b), LPS et al. through NF-jB, MAPK and PI3K/Akt/mTOR pathways. Besides, HIF-1’s transcriptional activity can also be increased by other proteins such as Cbx4 (a SUMO E3 ligase) in tumor cells. Current studies have shown that HIF-1 may contribute to angiogenesis from 3 aspects: 1) activating several angiogenic genes and their receptors; 2) regulating proangiogenic chemokines and receptors to recruit endothelial progenitor cells; 3) enhancing endothelial cells proliferation and division. HIF-1, hypoxia-inducible factor-1; TNF-a, tumor necrosis factor a; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; PDGFB, platelet-derived growth factor-b; SDF-1a, stromal cell derived factor 1a; CXCR4, C-X-C chemokine receptor type 4; S1P, sphingosine-1-phosphate; S1PRs, sphingosine-1-phosphate receptors; RA, rheumatoid arthritis.

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Fig. 2. The different roles of hypoxia-inducible factor-1 in different immune cells. (A) For macrophages, hypoxia or LPS stimulation can drive them into M1 macrophages, which rely on glycolysis for ATP production in HIF-1-dependent manner. M1 macrophages with high-level of IL-1b, iNOS and other classic pro-inflammatory cytokines are involved in against infection. In the memory function of innate immune system, known as trained immunity, HIF-1 also plays a vital role. A metabolic shift toward aerobic glycolysis can protect mice against sepsis through a dectin-1/Akt/mTOR/HIF-1 pathway. This phenomenon was observed during the monocyte-to-macrophage differentiation induced by bglucan training. (B) HIF-1 is also necessary for the expressions of costimulatory molecules CD80 and CD86 in DCs. HIF-1-deficent DCs are less well able to drive T-cell proliferation. (C) HIF-1 attenuates Tregs development by binding Foxp3 and targeting it for proteasomal degradation. Concurrently, HIF-1 enhances Th17 development through direct transcriptional activation of RORct, thereby increasing IL-17 expression. Glycolysis-mediated by HIF-1 enhances Th17 differentiation and causes Tregs to become inflammatory phenotype with high-expression of INF-c. MU, macrophages; LPS, lipopolysaccharide; ATP, adenosine triphosphate; HIF-1, hypoxia-inducible factor-1; IL, interleukin; iNOS, inducible nitric oxide synthase; mTOR, mammalian target of rapamycin; DCs, dendritic cells; Th, T helper cells; Tregs, regulatory T cells; INF-c, interferon c.

as Cbx4 (a SUMO E3 ligase) in tumor cells and then VEGF expression could be enhanced [35]. In ‘‘inflammatory hypoxia”, HIF-1 can be induced by lipopolysaccharide (LPS), metals, tumor necrosis factora (TNF-a) et al. [1,36]. LPS or some metal particles can active HIF-1 by enhancing reactive oxygen species (ROS) production. Then ROS initiates signaling cascades through mitogen-activated protein kinase (MAPK) and/or NF-jB pathways leading to HIF-1a stabilization and HIF-1 activation [1,36]. TNF-a enhances HIF-1 by multiple pathways including ROS and nitric oxide (NO) production, phosphoinositide 3-kinase (PI3K) and/or NF-jB activation [37,38]. Taken together, HIF-1 mediates angiogenesis occurring in both physiological and pathological states. However, inordinate high-level HIF-1 may contribute to the pathogenesis of diseases which are characterized by abnormal angiogenesis (Fig. 1). 2.2. HIF-1 and immune responses Ongoing inflammatory and immune responses are associated with increased oxygen consumption and accumulated HIF-1. Therefore it is not surprising that HIF-1 may participate in the reg-

ulation of immune responses. Macrophages and dendritic cells (DCs) are the frontline cells of innate immunity. For macrophages, hypoxia or LPS stimulation can drive them into M1 macrophages, which rely on glycolysis for adenosine triphosphate (ATP) production in HIF-1-dependent manner. M1 macrophages with high-level of IL (interleukin)-1b, inducible nitric oxide synthase (iNOS) and other classic pro-inflammatory cytokines are involved in against infection [22]. In the memory function of innate immune system, known as trained immunity, HIF-1 also plays a vital role. A metabolic shift toward aerobic glycolysis can protect mice against sepsis through a dectin-1/Akt/mammalian target of rapamycin (mTOR)/ HIF-1 pathway. This phenomenon was observed during the monocyte-to-macrophage differentiation induced by b-glucan training [39] (Fig. 2A). HIF-1 is also necessary for the expressions of co-stimulatory molecules CD80 and CD86 in DCs. HIF-1deficent DCs are less well able to drive T-cell proliferation [40,41] (Fig. 2B). Increasing evidences have shown that HIF-1 may play a key role in regulating the differentiation of T cells. Regulatory T cells (Tregs) are essential in preventing the immune system from attacking

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Fig. 3. The role of hypoxia-inducible factor-1 in fibrosis. First, HIF-1 may drive fibrogenesis through direct transcriptional regulations of profibrotic mediators (PDGF, FGF-2, and PAI-1, which containing HRE and being activated in an HIF-1-dependent manner). Another important mechanism underlying the pathogenesis of tissue fibrosis is EMT. HIF-1-Snail/Twist signaling can enhance expression of the mesenchymal markers. Epigenetic pathways may be involved in HIF-1-mediated-EMT. HIF-1, hypoxia-inducible factor-1; PDGF, platelet-derived growth factor; FGF-2, fibroblast growth factor-2; PAI-1, plasminogen activator inhibitor-1; HRE, hypoxia response element; a-SMA, a-smooth muscle actin.

self-tissues. HIF-1 attenuates Tregs development by binding Foxp3 and targeting it for proteasomal degradation. Concurrently, HIF-1 enhances Th17 development through direct transcriptional activation of RORct, thereby increasing IL-17 expression [21]. Glycolysismediated by HIF-1 enhances Th17 differentiation and causes Tregs to become inflammatory, leading to massive inflammatory diseases [8,42] (Fig. 2C). Not only in T cells themselves, but in other kind of cells, HIF-1 can regulate T cells as well. HIF-1 in DCs activates IL-10 production to promote the differentiation of Tregs, which is protective in colitis [43]. For tumor-infiltrating myeloidderived suppressor cells, HIF-1 caused a rapid, dramatic upregulation of programmed death ligand-1 (PD-L1) to suppress T cell activation [44]. Thus, both HIF-1 and HIF-1-mediated metabolic shift are crucial for immune systems.

2.3. HIF-1 and fibrosis Chronic hypoxia is increasingly recognized as an important determinant of fibrosis. HIF-1 has been demonstrated to be partly responsible for the onset and development of fibrosis [45]. Current studies have shown that HIF-1 can stimulate fibrosis by different mechanisms. First, HIF-1 may drive fibrogenesis through direct transcriptional regulations of pro-fibrotic mediators (PDGF, FGF2, fibroblast growth factor-2, PAI-1, plasminogen activator inhibitor-1, which containing HRE and being activated in an HIF-1-dependent manner) [46] (Fig. 3). Another important mechanism underlying the pathogenesis of tissue fibrosis is epithelial-mesenchymal transition (EMT), which has been shown to be crucial for renal fibrosis [47]. EMT is defined by the loss of epithelial cell polarity and cell–cell adhesion enabling these cells to migrate and acquire the invasive properties of mesenchymal cells [48]. HIF-1-Snail/Twist pathway and transforming growth factor b (TGF-b)-Smad pathway have shown to synergistically cooperate in EMT-mediated fibrosis. HIF-1-Snail/ Twist signaling can enhance expression of the mesenchymal markers (e.g. a-smooth muscle actin) [49,50]. A connection between HIF-1 and TGF-b-Smad signaling has been suggested because the DNA binding sites for HIF-1 and Smad are near one another in target genes (e.g. type I collagen) [51]. Epigenetic pathways may be involved in HIF-1-mediated-EMT. It has been reported that HIF1-induced histone deacetylase3 (HDAC3) can recruit the histone methyltransferase (HMT) complex to increase histone H3 lysine 4 (H3K4)-specific HMT activity, and activate mesenchymal gene expression [52]. Furthermore, HIF-1 can directly trans-activate

DNA methyltransferase 1 (DNMT1) and DNMT3B in cardiac fibroblasts to promote the expression of pro-fibrotic genes [48] (Fig. 3).

3. HIF-1 in autoimmune diseases 3.1. HIF-1 in RA RA is characterized by synovial tissue hyperplasia and immune cells infiltration, leading to joint destruction and functional disability [53,54]. Hypoxia has been identified as an important microenvironmental feature of RA [55–57]. HIF-1, possessing the central role in hypoxia adaptation, is strongly expressed in RA synovium [57–59], but not in patients with osteoarthritis (OA) [60]. The number of HIF-1-positive cells correlate strongly with the number of blood vessels in RA synovial tissues [61], suggesting that HIF-1 is involved in RA angiogenesis. VEGF, one of the most important angiogenesis factor, and its receptors are up-regulated in RA [56,62–67]. Inhibition of HIF-1 expression could significantly reduce VEGF-induced angiogenesis in RA fibroblasts [68], indicating that HIF-1/VEGF axis is an important angiogenesis pathway in RA. Besides VEGF, ephrin A3 (EFNA3), adipokines angiopoietinlike (ANGPTL)-4 and leptin, three pro-angiogenic factors, are also significantly induced depending on HIF-1 in RA fibroblast-like synoviocytes (FLS) [69]. In HIF-1-deficent macrophages collagen-induced arthritis (CIA) mice, infiltration of myeloid cells to the inflammatory site, paw swelling and the disease development are decreased [12], implying a role of HIF-1 in the onset of CIA inflammation and invasion. To support this notion, hypoxia-induced EMT has been observed in RA FLS with increased cell migration and invasion, which is associated with PI3K/Akt/HIF-1 pathway [70]. HIF-1 can mediate inflammation and invasion in RA in many aspects. For example, HIF-1 functions are correlated with toll-like receptor-stimulated innate immune responses [71], and necessary for TNF-a release [72]. HIF-1 over-expression enhances RA synovial fibroblasts-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory interferon (IFN)-c and IL-17 productions [71]. Moreover, it participates in a HIF-1/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA [73]. The family of metalloproteinases (MMPs), including MMP1, MMP2, MMP3, MMP9 and MMP13, also act in HIF-1-regulated tissue invasion [74–77]. HIF-1 participates in IL-1b-stimulating-MMP1/MMP13 and IL-17/TNF-a-promoting-MMP2/MMP9 expressions, resulting in greater migration and invasion abilities of RA FLS [74–76].

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Osteoclast activity disorder can result in pathological bone loss in RA. However, it is not well recognized how osteoclasts generate adequate ATP for the bone resorption in RA hypoxic microenvironment. One mechanism is that HIF-1 could mediate the metabolic switch to anaerobic respiration and enable osteoclasts to rapidly produce ATP in hypoxia status [78]. Additionally, mitochondrial mutagenesis and dysfunction are capable of being induced by hypoxia in RA synoviocytes, while DMOG, a HIF-1 stabilizer, could rescue these events [79]. All of these suggest that HIF-1 is necessary for osteoclasts and synoviocytes derived ATP generation in RA to result in pathological bone damage. The effects of HIF-1 in RA are regulated by a lot of factors. HIF10 s hydroxylase PHD2 is the major player to prevent HIF-1-induced angiogenesis [80]. Notch-1 could also mediate hypoxia-induced angiogenesis in RA via up-regulated HIF-1 expression [81]. HIF-1 and its downstream signal pathways are usually activated in hypoxia status, however, evidences have been presented that these factors could also be induced in normoxia [82,83]. For example, HIF-1 could be induced by Th1 cytokines, TNF-a and IL-1b, in both transcription and activity [69], and be modulated by proinflammatory cytokines. TNF-a and IL-1b are capable of activating and augmenting HIF-1 in normoxia, through activating MAPK, PI3K and NF-jB pathways [1,82,83], as well as direct binding the HIF-1 to the 50 promoter region [72]. Thus, these cytokines can induce the expressions of angiogenic and inflammatory factors, which contributing to the chronic autoimmune arthritis [84]. As one key role in RA pathogenesis, HIF-1 may become a promising target for RA treatment. Several novel compounds have been shown to act through targeting HIF-1 in the treatment of RA, in which 2-benzoyl-phenoxy acetamide could inhibit nuclear translocation of HIF-1 [85]. Ca2+/calmodulin-dependent protein kinase II (CaMKII), expressed in macrophages and fibroblasts in RA synovial tissue, is involved in HIF-1 stabilization [86,87]. SMP-114, as a novel CaMKII inhibitor, could suppress HIF-1 expression and significantly inhibit HIF-1-induced VEGF production in macrophages, whereas it had no effect in RA FLS in vitro [87,88]. Some active ingredients of Chinese herbs, such as Emodin (1,3,8-trihy-droxy-6-methyl-anthra quinone) that isolated from the root of Rheum palmatum L. and the anti-malarial agent artemisinin could also down-regulate HIF-1, VEGF and IL-8 in RA synoviocytes under hypoxia [89,90]. A green tea polyphenol, epigallocatechin-3-gallate (EGCG), suppresses the activation of mTOR and subsequently HIF-1, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis [91]. Meanwhile, TNF-a blocking therapy improves synovial tissue oxygen and reduces mitochondrial genome alterations in RA patients [92], supporting a role of these drugs in HIF-1 regulation. Although there have some candidates, it is still a long journey to find out effective drugs targeting on HIF-1 for bettering the life of RA patients. 3.2. HIF-1 in IBD IBD, including ulcerative colitis (UC) and Crohn’s disease (CD), has been demonstrated to have structural abnormalities in the microvasculature concurrent with tissue hypoxia [93]. As one of the important hypoxia regulated transcriptional factors, HIF-1 is consequently up-regulated in IBD. HIF-1 is highly expressed in surgical specimens from patients with active UC and CD [94]. But, unlike RA, in experimental colitis HIF-1 is mostly considered to be protective [24,93,95,96], and decreased HIF-1 expression is correlated with more severe clinical symptoms (mortality, weight loss, colon length) in vivo. When activating, HIF-1-regulated barrier-protective genes are increased, resulting in attenuated loss of barrier and promoted the mucosal healing [97]. The mechanisms for HIF-1-mediated protection have not been fully elucidated. It has been shown some pro-inflammatory cytoki-

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nes such as TNF-a, IFN-c and IL-1b are decreased in the presence of increased HIF-1 levels in murine colitis models [93,98]. Besides cytokines, a role of HIF-1 in the direct regulation of T cell subsets has been proposed. T cells, the prominent infiltrating cells in the inflamed mucosa in IBD, have been demonstrated to have a tight connection with HIF-1. Foxp3, a key transcriptional regulator for Tregs, could be selectively and robustly induced by hypoxia (1% oxygen), depending on HIF-1, and HIF-1-deficient Tregs fail to control T-cell-mediated colitis [96]. Meanwhile, Th1 and Th17 are increased after the administration of dextran-sodium sulfate to T cell-specific HIF-1 KO mice, leading to more severe colonic inflammation [99]. Not only HIF-1 in T cells, HIF-1 in DCs activates IL-10 production to promote the differentiation of Tregs, which is protective in colitis [43]. The phagocytosis of apoptotic neutrophils by macrophages is also enhanced by HIF-1-mediated pathway in vitro, suggesting HIF-1 may constitute a crucial role in innate immunity to accelerate the mucosa healing of IBD [100]. Based on the protective role of HIF-1 in IBD, stabilizing HIF-1 has been tried for IBD treatment. The hydroxylase inhibitor DMOG could down-regulate intestinal epithelial cell apoptosis through HIF-1/NF-jB pathway [95]. DMOG also abrogates TNF-a-induced intestinal epithelial damage by HIF-1-dependent repression of Fas-associated death domain protein (FADD), a critical adaptor molecule in tumor necrosis factor receptor-1 (TNFR-1)-mediated apoptosis [101]. In addition, PHD inhibitors, FG-4497, AKB-4924 and TRC160334 could provide an overall beneficial influence on innate immunity and clinical symptoms (weight loss, colon length, epithelial barrier function and TNF-a) in murine colitis [93,102,103]. Further work is required to find out the patented mechanisms of relationship between HIF-1 and IBD, as well as applicable treatment. 3.3. HIF-1 in psoriasis Psoriasis is a common chronic inflammatory disorder mainly involving skin. It is characterized by enhanced angiogenesis, proliferation of keratinocytes and infiltrating immune cells [104]. In psoriasis, skin hypoxia is intensified and HIF-1 is increased in both skin and serum [25,105] and the crucial contributor of HIF-1 degradation, VHL is decreased [106], supporting that HIF-1 participates in the pathogenesis of psoriasis. However, it is still unclear how this factor works. As mentioned before, HIF-1 is tightly correlated with generation of neovessels, and the same is true for psoriasis. VEGF and its receptor VEGFR-1 are up-regulated in psoriatic skin [107]. The expression of VEGF is enhanced depending on increased HIF-1 in both human keratinocyte cell line HaCaT and psoriatic skin [108,109], suggesting HIF-1 may act through VEGF to enhance angiogenesis in psoriasis [110]. Meanwhile, glucose transporter member 1 (GLUT-1) protein, one target gene of HIF-1 involved in the proliferation of epidermal keratinocytes in psoriasis, is increased in psoriasis lesion [111]. GLUT-1-related proliferation of epidermal keratinocytes is also dependent on HIF-1 [112]. Chronic inflammation is an important characteristic of psoriasis [113]. HIF-1 is necessary for the productions of TNF-a, IL-6, cxc chemokine ligand (CXCL) 8 and cathelicidin LL-37, which contributing to the chronic skin inflammation [105,114]. Recent studies have shown that Th17 cells are related to the development of autoimmune and inflammatory diseases [115]. In psoriasis patients, Th17 cells are increased in psoriatic lesions and in circulation [116]. Th17 cells can induce the production of inflammatory cytokines, as IL-6 and IL-8, in keratinocytes [117]. According to this, Th17 acts as an important role to keep the chronic inflammation in psoriasis. For the Th17 differentiation, HIF-1 enhances Th17 development through direct transcriptional activation of RORct, thereby increasing IL-17 expression [21]. Glycolysis-mediated by

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HIF-1 enhances Th17 differentiation and causes Tregs to become inflammatory phenotype with high-expression of INF-c [8,42]. These results suggest that HIF-1 induces inflammatory cytokines generation and favors the polarization of Th17 cells, which may result in the chronic inflammation in psoriasis. Recent studies suggest that HIF-1 may be a promising target for treatment of psoriasis. Extracellular superoxide dismutase (ECSOD) is an antioxidant enzyme that could suppress angiogenesis and inflammatory in hypoxia-induced keratinocytes and in ultraviolet B-irradiated mice, which is mediated by the suppression of HIF-1 [118]. Besides, through down-regulating translation of HIF-1 in psoriatic epidermis, capsaicin ointment could inhibit proliferation and induce differentiation of keratinocytes [119]. However, HIF-1 inhibitors have not yet been applied to psoriasis either in vivo or in vitro directly. The exact role of HIF-1 in pathogenesis of psoriasis will still require extensive researches.

HIF-1-induced EPO shows protective through promoting Schwann cell survival, myelin production, and Tregs differentiation [133]. On the other hand, HIF-1 may be involved in IL-1b pathway or metabolic reprogramming of CD4+ T cells to increase blood-brain barrier permeability or T cell activation in MS [134,135], thus may have an opposite role in MS. 4. Conclusion HIF-1 is the important bond between inflammatory and hypoxia. It participates in the autoimmune diseases mainly in two aspects: 1) promoting angiogenesis, and 2) regulating inflammatory, immune cells and some cytokines. Besides, HIF-1-mediated metabolic shift and fibrosis may also play crucial roles in some autoimmune disorders. The features of HIF-1 prompt it to be a promising therapeutic target for autoimmune diseases.

3.4. HIF-1 in SSc Competing interests Vascular alterations, immunological disturbances and fibrosis of the skin and internal organs are the striking characteristics of SSc. It has been demonstrated that the oxygen level in SSc skin is reduced [120], prompting a role of HIF-1 in SSc. Skin biopsies from untreated scleroderma patients confirm the strong expression of HIF-1 and VEGF in comparison with rare immunoreactivity observed in normal skin [121]. However, the elevated levels of VEGF do not result in sufficient angiogenesis. A reason for the ineffectiveness of VEGF could be that the time being close to the active angiogenic compartment is too short, resulting in instable vessels [122]. Moreover, isolated microvascular endothelial cells from SSc patients show an impaired response to VEGF and other growth factors [122]. The expression of the fibrogenic cytokine connective tissue growth factor (CTGF) and major extracellular matrix proteins are increased by HIF-1-dependent mechanisms, contributing to the fibrosis in SSc [123,124]. Moreover, a single nucleotide polymorphisms analysis in European Caucasian population shows that SSc patients have an increased presence of a genetic variant of HIF1, supporting a role for HIF-1 in the etiology of SSc [125]. However, there is also some dispute about HIF-1 in SSc and the factor has been reported to decrease in the epidermis of SSc patients compared to healthy controls [26], which might be due to a negative feedback loop causing an increase in PHD and resulting in a faster degradation of HIF-1 [120,126]. 3.5. HIF-1 in MS MS is a chronic inflammatory demyelinating disease of central nervous system. Although hypoxia seems not play a role in the onset of MS, there are still evidences suggesting HIF-1 participating in MS progress [27]. In the spine cord of mice with chronic experimental autoimmune encephalomyelitis (EAE), an animal model of MS, HIF-1 level is increased, and correlates with the up-regulated erythropoietin (EPO), which is a protective factor in EAE [127]. Furthermore, HIF-1 is also accumulated in the brains of post-mortem MS patients [128]. The function of HIF-1 in MS is still swing. Most studies have supported that HIF-1 is protective in MS [27,129–132]. In Balo’s type of MS, HIF-1 is expressed mainly in oligodendrocytes, and HIF-10 s neuroprotective effects may assist periplaque tissue in resisting to further damages [129]. Besides, the increased of HIF1 stability could protect oligodendrocytes against LPS-mediated injury and TNF-a-mediated cell death [27,130]. Methylprednisolone, a widely used glucocorticoid for treating MS, protects oligodendrocytes from excitotoxicity, depending on HIF-1-related pathway as well [132]. In another human demyelinating inflammatory disease of the peripheral nervous system animal model,

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