Research Progress of Hypoxia Inducible Factor in Inflammatory Diseases

: Mesenchymal stem cell (MSC) therapy for clinical diseases associated with inflammation and tissue damage has become a progressive treatment strategy. MSCs have unique biological functions, such as homing, immune regulation, and differentiation capabilities, which provide the prerequisites for treatment of clinical diseases. Oral diseases are often associated with abnormal immune regulation and epithelial tissue damage. In this review, we summarize previous studies that use MSC therapy to treat various oral inflammatory diseases, including oral ulceration, allergic diseases, chemo/radiotherapy-induced oral mucositis, periodontitis, osteonecrosis of the jaw, Sjögren's syndrome (SS), among other similar diseases. We highlight MSC treatment as a promising approach in the management of oral inflammatory diseases, and discuss the obstacles that remain and must be overcome for MSC treatment to thrive in the future.

Download Full-text

Natural Products for Regulating Macrophages M2 Polarization

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190523093535 ◽

2020 ◽

Vol 15 (7) ◽

pp. 559-569 ◽

Cited By ~ 1

Author(s):

Zhen Chang ◽

Youhan Wang ◽

Chang Liu ◽

Wanli Smith ◽

Lingbo Kong

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Research Progress ◽

Cellular Mechanisms ◽

Pharmacological Activities ◽

Current Review ◽

M2 Polarization ◽

Macrophages Polarization ◽

Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

Download Full-text

Determinants of hypoxia-inducible factor activity in the intestinal mucosa

Journal of Applied Physiology ◽

10.1152/japplphysiol.00203.2017 ◽

2017 ◽

Vol 123 (5) ◽

pp. 1328-1334 ◽

Cited By ~ 4

Author(s):

Raphael R. Fagundes ◽

Cormac T. Taylor

Keyword(s):

Intestinal Mucosa ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Oxygen Demand ◽

Intestinal Lumen ◽

Adaptation To Hypoxia ◽

Healthy Mucosa ◽

Microenvironmental Factors ◽

Anoxic Environment

The intestinal mucosa is exposed to fluctuations in oxygen levels due to constantly changing rates of oxygen demand and supply and its juxtaposition with the anoxic environment of the intestinal lumen. This frequently results in a state of hypoxia in the healthy mucosa even in the physiologic state. Furthermore, pathophysiologic hypoxia (which is more severe and extensive) is associated with chronic inflammatory diseases including inflammatory bowel disease (IBD). The hypoxia-inducible factor (HIF), a ubiquitously expressed regulator of cellular adaptation to hypoxia, is central to both the adaptive and the inflammatory responses of cells of the intestinal mucosa in IBD patients. In this review, we discuss the microenvironmental factors which influence the level of HIF activity in healthy and inflamed intestinal mucosae and the consequences that increased HIF activity has for tissue function and disease progression.

Download Full-text

Research Progress of Hypoxia Inducible Factor-2 in Head and Neck Tumors

Advances in Clinical Medicine ◽

10.12677/acm.2020.1010357 ◽

2020 ◽

Vol 10 (10) ◽

pp. 2367-2371

Author(s):

伟高

Keyword(s):

Head And Neck ◽

Hypoxia Inducible Factor ◽

Head And Neck Tumors ◽

Research Progress ◽

Neck Tumors

Download Full-text

HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

Blood ◽

10.1182/blood-2007-10-115758 ◽

2008 ◽

Vol 111 (7) ◽

pp. 3343-3354 ◽

Cited By ~ 89

Author(s):

Marzia Scortegagna ◽

Christophe Cataisson ◽

Rebecca J. Martin ◽

Daniel J. Hicklin ◽

Robert D. Schreiber ◽

...

Keyword(s):

Transgenic Mice ◽

Cancer Metastasis ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Local Environment ◽

Inflammatory Cells ◽

Hypoxia Inducible Factor 1 ◽

Inflammatory Protein ◽

Multiple Cell ◽

Epithelial Inflammation

AbstractHypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.

Download Full-text

Asaronic Acid Suppresses Diabetic Macrophage Activation Toward M1 Phenotype Through Inhibition of NF-κB Pathway and JAK-STAT Signaling in Glucose-loaded Macrophages (P06-067-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-067-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Hyeongjoo Oh ◽

Young-Hee Kang

Keyword(s):

Macrophage Activation ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Funding Sources ◽

Metabolic Defects ◽

M1 Macrophage ◽

Inflammatory Activation ◽

Stat Signaling ◽

Inflammatory State ◽

M1 Phenotype

Abstract Objectives Macrophage activation has become implicated in the pathogenesis of obesity and type 2 diabetes that are now recognized as chronic pro-inflammatory diseases. However, the mechanisms by which macrophages mediated the enhanced inflammation associated with metabolic defects are not completely understood.This study examined whether 1–20 μM asaronic acid (2,4,5-trimethoxybenzoic acid), identified as one of purple perilla constituents, counteracted inflammatory activation of diabetic macrophages with M1 phenotypes through blocking NF-κB pathway/JAK-STAT signaling. Methods J774A.1 murine macrophages were incubated with 2 μg/ml lipopolysaccharide (LPS) or 33 mM glucose in the absence and presence of 1–20 μΜ asaronic acid, which led to M1 or diabetic inflammatory state at 48 h. The M1 macrophage biomarkers were estimated by conducting Western blot analysis, IHC and ELISA with specific antibodies. Asaronic acid at ≤20 μM was nontoxic during 72 h-incubation. Results The presence of asaronic acid reduced the LPS-promoted secretion of pro-inflammatory IL-6 and MCP-1. LPS elevated the induction of the M1 markers of toll-like receptor 4, CD36 and CD68 in macrophages. The LPS exposure to macrophages enhanced NF-κB transactivation, STAT1/STAT3 activation and SOCS3 induction. However, asaronic acid suppressed the aforementioned effects of LPS. On the other hand, high glucose stimulated macrophages to express advanced glycation end products, receptor for AGE , hypoxia inducible factor-1α and VEGF. Furthermore, glucose enhanced the induction of TLR4 and inducible nitric oxide synthase and IL-6 production in macrophages. Asaronic acid encumbered NF-κB transactivation, activation of JAK2, STAT1/STAT3, and SOCS3 induction in glucose- supplemented macrophages. Conclusions These results clearly demonstrated for the first time that asaronic acid may limit diabetic inflammatory activation of macrophages toward the M1 phenotype through inhibition of TLR4- and IL-6-mediated NF-κB pathway/JAK-STAT signaling entailing AGE-RAGE interaction. Funding Sources This work (Grants No. C0501612) was supported by project for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Ministry of SMEs and Startups in 20.

Download Full-text

HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA–forming microsatellite

Blood ◽

10.1182/blood-2006-12-063289 ◽

2007 ◽

Vol 110 (8) ◽

pp. 3039-3048 ◽

Cited By ~ 50

Author(s):

Henry K. Bayele ◽

Carole Peyssonnaux ◽

Alexandra Giatromanolaki ◽

Wagner W. Arrais-Silva ◽

Hiba S. Mohamed ◽

...

Keyword(s):

Disease Risk ◽

Allelic Variation ◽

Inflammatory Diseases ◽

Inbred Mice ◽

Hypoxia Inducible Factor ◽

Immune Response Gene ◽

Allelic Association ◽

Heritable Variation ◽

Allele Expression ◽

Z Dna

AbstractThe Ity/Lsh/Bcg locus encodes the macrophage protein Slc11a1/Nramp1, which protects inbred mice against infection by diverse intracellular pathogens including Leishmania, Mycobacterium, and Salmonella. Human susceptibility to infectious and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and tuberculosis, shows allelic association with a highly polymorphic regulatory, Z-DNA–forming microsatellite of (GT/AC)n dinucleotides within the proximal SLC11A1 promoter. We surmised that cis-acting allelic polymorphisms may underlie heritable differences in SLC11A1 expression and phenotypic variation in disease risk. However, it is unclear what may underlie such variation in SLC11A1 allele expression. Here we show that hypoxia-inducible Factor 1 (HIF-1) regulates allelic variation in SLC11A1 expression by binding directly to the microsatellite during macrophage activation by infection or inflammation. Targeted Hif-1α ablation in murine macrophages attenuated Slc11a11 expression and responsiveness to S typhimurium infection. Our data also showed that HIF-1 may be functionally linked to complex prototypical inflammatory diseases associated with certain SLC11A1 alleles. As these alleles are highly polymorphic, our finding suggests that HIF-1 may influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation within and between populations. This report also suggests that microsatellites may play critical roles in the directional evolution of complex heritable traits by regulating gene expression phenotypes.

Download Full-text

Activation of HIF-1α does not increase intestinal tumorigenesis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00112.2014 ◽

2014 ◽

Vol 307 (2) ◽

pp. G187-G195 ◽

Cited By ~ 31

Author(s):

Xiang Xue ◽

Sadeesh K. Ramakrishnan ◽

Yatrik M. Shah

Keyword(s):

Colon Cancer ◽

Transcription Factors ◽

Cancer Progression ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Cell Metabolism ◽

Tumor Biology ◽

Hypoxia Inducible Factor ◽

Pharmacological Agents ◽

Epithelial Barrier Function

The hypoxic response is mediated by two transcription factors, hypoxia-inducible factor (HIF)-1α and HIF-2α. These highly homologous transcription factors are induced in hypoxic foci and regulate cell metabolism, angiogenesis, cell proliferation, and cell survival. HIF-1α and HIF-2α are activated early in cancer progression and are important in several aspects of tumor biology. HIF-1α and HIF-2α have overlapping and distinct functions. In the intestine, activation of HIF-2α increases inflammation and colon carcinogenesis in mouse models. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1α is beneficial and can reduce intestinal inflammation. HIF-1α is a critical transcription factor regulating epithelial barrier function following inflammation. The beneficial value of pharmacological agents that chronically activate HIF-1α is decreased due to the tumorigenic potential of HIFs. The present study tested the hypothesis that chronic activation of HIF-1α may enhance colon tumorigenesis. Two models of colon cancer were assessed, a sporadic and a colitis-associated colon cancer model. Activation of HIF-1α in intestinal epithelial cells does not increase carcinogenesis or progression of colon cancer. Together, the data provide proof of principle that pharmacological activation of HIF-1α could be a safe therapeutic strategy for inflammatory bowel disease.

Download Full-text

Ginsenoside Rh2 Downregulates LPS-Induced NF-κB Activation through Inhibition of TAK1 Phosphorylation in RAW 264.7 Murine Macrophage

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/646728 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Li-Hua Lian ◽

Quan Jin ◽

Shun-Zong Song ◽

Yan-Ling Wu ◽

Ting Bai ◽

...

Keyword(s):

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Nuclear Factor ◽

Ginsenoside Rh2 ◽

Toll Like Receptor ◽

Inhibitory Effects ◽

Toll Like Receptor 4 ◽

Time Period

The present study was carried out to evaluate the inhibitory effects of ginsenoside Rh2 on nuclear-factor- (NF-)κB in lipopolysaccharide- (LPS-) activated RAW 264.7 murine macrophages. RAW 264.7 cells were pretreated with indicated concentrations of ginsenoside Rh2 for 1 h prior to the incubation of LPS (1 μg/mL) for indicated time period. Ginsenoside Rh2 reduced CD14 and Toll-like receptor 4 (TLR4) expressions 24 h after LPS stimulation. Furthermore, ginsenoside Rh2 significantly inhibited TGF-beta-activated kinase 1 (TAK1) phosphorylation 30 min after LPS stimulation. Ginsenoside Rh2 was further shown to inhibit NF-κB p65 translocation into the nucleus by suppressing IκB-αdegradation. Also, LPS increased mRNA expression of TNF-αand IL-1αtime-dependently, while TQ reduced TNF-αwithin 3 h and IL-1αwithin 1 h. And we firstly found that pretreatment of ginsenoside Rh2 successively inhibited hypoxia-inducible factor- (HIF-) 1αexpression increased by LPS. In conclusion, ginsenoside Rh2 may inhibit LPS-induced NF-κB activation and reduce HIF-1αaccumulation, suggesting that ginsenoside Rh2 may be considered as a potential therapeutic candidate for chronic inflammatory diseases.

Download Full-text

Neddylation pathway alleviates chronic pancreatitis by reducing HIF1α-CCL5-dependent macrophage infiltration

Cell Death and Disease ◽

10.1038/s41419-021-03549-3 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Yuli Lin ◽

Yusheng Chen ◽

Wenxue Feng ◽

Rong Hua ◽

Junfeng Zhang ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Disease Treatment ◽

Inflammatory Microenvironment ◽

Mechanistic Investigation ◽

Wide Range ◽

New Ideas

AbstractChronic pancreatitis (CP) is characterized by a wide range of irreversible fibro-inflammatory diseases with largely ambiguous pathogenesis. Although neddylation pathway has been implicated in regulating immune responses, whether the dysregulation of neddylation is involved in the progression of CP and how neddylation regulates the inflammatory microenvironment of CP have not yet been reported. Here, we demonstrate that global inactivation of neddylation pathway by MLN4924 significantly exacerbates chronic pancreatitis. The increased M2 macrophage infiltration, mediated by the upregulated chemokine (C-C motif) ligand 5 (CCL5), is responsible for the enhanced pancreatitis-promoting activity of MLN4924. Both CCL5 blockade and macrophage depletion contribute to alleviating pancreatic fibrosis and inflammation in MLN4924-treated CP mice. Mechanistic investigation identifies that inactivation of Cullin-RING ligases (CRLs) stabilizes cellular levels of hypoxia-inducible factor 1α (HIF-1α), which increases CCL5 expression by promoting CCL5 transactivation. Clinically, UBE2M expression remarkably decreases in human CP tissues compared with normal specimens and the levels of CCL5 and M2 marker CD163 are negatively correlated with UBE2M intensity, suggesting that neddylation is involved in the pathogenesis of pancreatitis. Hence, our studies reveal a neddylation-associated immunopathogenesis of chronic pancreatitis and provide new ideas for the disease treatment.

Download Full-text