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Enlightening the role of high mobility group box 1 (HMGB1) in inflammation: Updates on receptor signalling

Paudel YN, Angelopoulou E, Piperi C, Balasubramaniam VRMT, Othman I, Shaikh MF

Eur J Pharmacol, 2019 Sep 05;858:172487.
PMID: 31229535 DOI: 10.1016/j.ejphar.2019.172487

High mobility group box 1 (HMGB1) is a ubiquitous protein, released passively by necrotic tissues or secreted actively by stressed cells. Extracellular HMGB1 is a typical damage-associated molecular pattern (DAMP) molecule which generates different redox types through binding with several receptors and signalling molecules, aggravating a range of cellular responses, including inflammation. HMGB1 is reported to participate in the pathogenesis of inflammatory diseases, through the interaction with pivotal transmembrane receptors, including the receptor for advanced glycation end products (RAGE) and toll-like receptor-4 (TLR-4). This review aims to highlight the role of HMGB1 in the innate inflammatory response describing its interaction with several cofactors and receptors that coordinate its downstream effects. Novel and underexplored HMGB1 binding molecules that have been actively involved in HMGB1-mediated inflammatory diseases/conditions with therapeutic potential are further discussed.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Gonadotropin-inhibitory hormone mediates behavioral stress responses

Ubuka T, Parhar IS, Tsutsui K

Gen Comp Endocrinol, 2018 09 01;265:202-206.
PMID: 29510150 DOI: 10.1016/j.ygcen.2018.03.004

Gonadotropin-inhibitory hormone (GnIH) is an inhibitor of the hypothalamic-pituitary-gonadal (HPG) axis. GnIH is also called RFamide-related peptide (RFRP) as GnIH peptides have a characteristic C-terminal LPXRFiamide (X = L or Q) sequence. GnIH is thought to be the mediator of stress by negatively regulating the HPG axis as various stressors increase GnIH mRNA, GnIH peptide or GnIH neuronal activity. On the other hand, GnIH may also mediate behavioral stress responses as GnIH neuronal fibers and GnIH receptors are widely located in the limbic system of telencephalon, diencephalon and midbrain area. Previous studies have shown that intracerebroventricular (i.c.v.) administration of GnIH (RFRP) blocks morphine-induced analgesia in hot plate and formalin injection tests in rats suggesting that GnIH increases sensitivity to pain. GnIH (RFRP) also increases anxiety-like behavior in rats. RNA interference of GnIH gene (GnIH RNAi) increases locomotor activity of white-crowned sparrow and Japanese quail and i.c.v. administration of GnIH decreases GnIH RNAi induced locomotor activity. It was further shown that i.c.v. administration of GnIH (RFRP) decreases aggressive behavior in male quail and sexual behavior in male rats, female white-crowned sparrow and female hamsters. These results suggest that GnIH decreases threat to homeostasis of the organism by increasing pain sensitivity, anxiety and decreasing locomotor activity, aggressive behavior and sexual behavior. GnIH may also mediate the effect of stress on behavior.

Matched MeSH terms: Receptors, Cell Surface/metabolism
Fulltext Overview of the Microenvironment of Vasculature in Vascular Tone Regulation

Loh YC, Tan CS, Ch'ng YS, Yeap ZQ, Ng CH, Yam MF

Int J Mol Sci, 2018 Jan 02;19(1).
PMID: 29301280 DOI: 10.3390/ijms19010120

Hypertension is asymptomatic and a well-known "silent killer", which can cause various concomitant diseases in human population after years of adherence. Although there are varieties of synthetic antihypertensive drugs available in current market, their relatively low efficacies and major application in only single drug therapy, as well as the undesired chronic adverse effects associated, has drawn the attention of worldwide scientists. According to the trend of antihypertensive drug evolution, the antihypertensive drugs used as primary treatment often change from time-to-time with the purpose of achieving the targeted blood pressure range. One of the major concerns that need to be accounted for here is that the signaling mechanism pathways involved in the vasculature during the vascular tone regulation should be clearly understood during the pharmacological research of antihypertensive drugs, either in vitro or in vivo. There are plenty of articles that discussed the signaling mechanism pathways mediated in vascular tone in isolated fragments instead of a whole comprehensive image. Therefore, the present review aims to summarize previous published vasculature-related studies and provide an overall depiction of each pathway including endothelium-derived relaxing factors, G-protein-coupled, enzyme-linked, and channel-linked receptors that occurred in the microenvironment of vasculature with a full schematic diagram on the ways their signals interact. Furthermore, the crucial vasodilative receptors that should be included in the mechanisms of actions study on vasodilatory effects of test compounds were suggested in the present review as well.

Matched MeSH terms: Receptors, Cell Surface/metabolism
Fulltext Roles of Sema4D and Plexin-B1 in tumor progression

Ch'ng ES, Kumanogoh A

Mol. Cancer, 2010;9:251.
PMID: 20858260 DOI: 10.1186/1476-4598-9-251

Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Fulltext Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi

Kosaisavee V, Suwanarusk R, Chua ACY, Kyle DE, Malleret B, Zhang R, et al.

Blood, 2017 09 14;130(11):1357-1363.
PMID: 28698207 DOI: 10.1182/blood-2017-02-764787

Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe postinvasion morphologic and rheologic alterations in P cynomolgi-infected human reticulocytes that are strikingly similar to those observed for P vivax These observations stress the value of P cynomolgi as a model in the development of blood stage vaccines against vivax malaria.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Fulltext Two Genetically Distinct Plasmodium knowlesi Duffy Binding Protein Alpha Region II (PkDBPαII) Haplotypes Demonstrate Higher Binding Level to Fy(a+b+) Erythrocytes than Fy(a+b--) Erythrocytes

Liew CC, Lau YL, Fong MY, Cheong FW

Am J Trop Med Hyg, 2020 05;102(5):1068-1071.
PMID: 32189613 DOI: 10.4269/ajtmh.19-0836

Invasion of human erythrocytes by merozoites of Plasmodium knowlesi involves interaction between the P. knowlesi Duffy binding protein alpha region II (PkDBPαII) and Duffy antigen receptor for chemokines (DARCs) on the erythrocytes. Information is scarce on the binding level of PkDBPαII to different Duffy antigens, Fya and Fyb. This study aims to measure the binding level of two genetically distinct PkDBPαII haplotypes to Fy(a+b-) and Fy(a+b+) human erythrocytes using erythrocyte-binding assay. The binding level of PkDBPαII of Peninsular Malaysian and Malaysian Borneon haplotypes to erythrocytes was determined by counting the number of rosettes formed in the assay. Overall, the Peninsular Malaysian haplotype displayed higher binding activity than the Malaysian Borneon haplotype. Both haplotypes exhibit the same preference to Fy(a+b+) compared with Fy(a+b-), hence justifying the vital role of Fyb in the binding to PkDBPαII. Further studies are needed to investigate the P. knowlesi susceptibility on individuals with different Duffy blood groups.

Matched MeSH terms: Receptors, Cell Surface/metabolism
Fulltext Erythrocyte-binding assays reveal higher binding of Plasmodium knowlesi Duffy binding protein to human Fya+/b+ erythrocytes than to Fya+/b- erythrocytes

Fong MY, Cheong FW, Lau YL

Parasit Vectors, 2018 Sep 26;11(1):527.
PMID: 30257710 DOI: 10.1186/s13071-018-3118-8

BACKGROUND: The merozoite of the zoonotic Plasmodium knowlesi invades human erythrocytes via the binding of its Duffy binding protein (PkDBPαII) to the Duffy antigen on the eythrocytes. The Duffy antigen has two immunologically distinct forms, Fya and Fyb. In this study, the erythrocyte-binding assay was used to quantitatively determine and compare the binding level of PkDBPαII to Fya+/b+ and Fya+/b- human erythrocytes.
RESULTS: In the erythrocyte-binding assay, binding level was determined by scoring the number of rosettes that were formed by erythrocytes surrounding transfected mammalian COS-7 cells which expressed PkDBPαII. The assay result revealed a significant difference in the binding level. The number of rosettes scored for Fya+/b+ was 1.64-fold higher than that of Fya+/b- (155.50 ± 34.32 and 94.75 ± 23.16 rosettes, respectively; t(6) = -2.935, P = 0.026).
CONCLUSIONS: The erythrocyte-binding assay provided a simple approach to quantitatively determine the binding level of PkDBPαII to the erythrocyte Duffy antigen. Using this assay, PkDBPαII was found to display higher binding to Fya+/b+ erythrocytes than to Fya+/b- erythrocytes.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Fulltext In silico prediction of interaction between Nipah virus attachment glycoprotein and host cell receptors Ephrin-B2 and Ephrin-B3 in domestic and peridomestic mammals

Hoque AF, Rahman MM, Lamia AS, Islam A, Klena JD, Satter SM, et al.

Infect Genet Evol, 2023 Dec;116:105516.
PMID: 37924857 DOI: 10.1016/j.meegid.2023.105516

Nipah virus (NiV) is a lethal bat-borne zoonotic virus that causes mild to acute respiratory distress and neurological manifestations in humans with a high mortality rate. NiV transmission to humans occurs via consumption of bat-contaminated fruit and date palm sap (DPS), or through direct contact with infected individuals and livestock. Since NiV outbreaks were first reported in pigs from Malaysia and Singapore, non-neutralizing antibodies against NiV attachment Glycoprotein (G) have also been detected in a few domestic mammals. NiV infection is initiated after NiV G binds to the host cell receptors Ephrin-B2 and Ephrin-B3. In this study, we assessed the degree of NiV host tropism in domestic and peridomestic mammals commonly found in Bangladesh that may be crucial in the transmission of NiV by serving as intermediate hosts. We carried out a protein-protein docking analysis of NiV G complexes (n = 52) with Ephrin-B2 and B3 of 13 domestic and peridomestic species using bioinformatics tools. Protein models were generated by homology modelling and the structures were validated for model quality. The different protein-protein complexes in this study were stable, and their binding affinity (ΔG) scores ranged between -8.0 to -19.1 kcal/mol. NiV Bangladesh (NiV-B) strain displayed stronger binding to Ephrin receptors, especially with Ephrin-B3 than the NiV Malaysia (NiV-M) strain, correlating with the observed higher pathogenicity of NiV-B strains. From the docking result, we found that Ephrin receptors of domestic rat (R. norvegicus) had a higher binding affinity for NiV G, suggesting greater susceptibility to NiV infections compared to other study species. Investigations for NiV exposure to domestic/peridomestic animals will help us knowing more the possible role of rats and other animals as intermediate hosts of NiV and would improve future NiV outbreak control and prevention in humans and domestic animals.

Matched MeSH terms: Receptors, Cell Surface/metabolism
The mRNA expression of soluble urokinase plasminogen activator surface receptor in human adipose tissue is positively correlated with body mass index

Ng HF, Chin KF, Chan KG, Ngeow YF

Genome, 2015 Jun;58(6):315-21.
PMID: 26284904 DOI: 10.1139/gen-2015-0028

suPLAUR is the transcript variant that encodes the soluble form of the urokinase plasminogen activator surface receptor (suPLAUR). This soluble protein has been shown to enhance leukocyte migration and adhesion, and its circulatory level is increased in inflammatory states. In this pilot study, we used RNA-Seq to examine the splicing pattern of PLAUR in omental adipose tissues from obese and lean individuals. Of the three transcript variants of the PLAUR gene, only the proportion of suPLAUR (transcript variant 2) increases in obesity. After removing the effects of gender and age, the expression of suPLAUR is positively correlated with body mass index. This observation was validated using RT-qPCR with an independent cohort of samples. Additionally, in our RNA-Seq differential expression analysis, we also observed, in obese adipose tissues, an up-regulation of genes encoding other proteins involved in the process of chemotaxis and leukocyte adhesion; of particular interest is the integrin beta 2 (ITGB2) that is known to interact with suPLAUR in leukocyte adhesion. These findings suggest an important role for suPLAUR in the recruitment of immune cells to obese adipose tissue, in the pathogenesis of obesity.

Matched MeSH terms: Receptors, Cell Surface/metabolism
Differentiation of human mesenchymal stem cells into mesangial cells in post-glomerular injury murine model

Wong CY, Cheong SK, Mok PL, Leong CF

Pathology, 2008 Jan;40(1):52-7.
PMID: 18038316

AIMS: Adult human bone marrow contains a population of mesenchymal stem cells (MSC) that contributes to the regeneration of tissues such as bone, cartilage, muscle, tendon, and fat. In recent years, it has been shown that functional stem cells exist in the adult bone marrow, and they can contribute to renal remodelling or reconstitution of injured renal glomeruli, especially mesangial cells. The purpose of this study is to examine the ability of MSC isolated from human bone marrow to differentiate into mesangial cells in glomerular injured athymic mice.
METHODS: MSC were isolated from human bone marrow mononuclear cells based on plastic adherent properties and expanded in vitro in the culture medium. Human mesenchymal stem cells (hMSC) were characterised using microscopy, immunophenotyping, and their ability to differentiate into adipocytes, chondrocytes, and osteocytes. hMSC were then injected into athymic mice, which had induced glomerulonephropathy (GN).
RESULTS: Test mice (induced GN and infused hMSC) were shown to have anti-human CD105(+) cells present in the kidneys and were also positive to anti-human desmin, a marker for mesangial cells. Furthermore, immunofluorescence assays also demonstrated that anti-human desmin(+) cells in the glomeruli of these test mice were in the proliferation stage, being positive to anti-human Ki-67.
CONCLUSIONS: These findings indicate that hMSC found in renal glomeruli differentiated into mesangial cells in vivo after glomerular injury occurred.

Matched MeSH terms: Receptors, Cell Surface/metabolism
In vitro inhibitory effect of rubraxanthone isolated from Garcinia parvifolia on platelet-activating factor receptor binding

Jantan I, Pisar MM, Idris MS, Taher M, Ali RM

Planta Med, 2002 Dec;68(12):1133-4.
PMID: 12494345

Rubraxanthone and isocowanol isolated from Garcinia parvifolia Miq. were investigated for their inhibitory effects on platelet-activating factor (PAF) binding to rabbit platelets using 3H-PAF as a ligand. Rubraxanthone showed a strong inhibition with IC 50 value of 18.2 microM. The IC 50 values of macluraxanthone, 6-deoxyjacareubin, 2-(3-methylbut-2-enyl)-1,3,5-trihydroxyxanthone, 2-(3-methylbut-2-enyl)-1,3,5,6-tetrahydroxyxanthone and 1,3,5-trihydroxy-6,6'-dimethylpyrano(2',3':6,7)-4-(1,1-dimethylprop-2-enyl)-xanthone were also determined for comparison. In the course of our study on structure-activity relationship of xanthones, the results revealed that a geranyl group substituted at C-8 was beneficial to the binding while a hydroxylated prenyl group at C-4 resulted in a significant loss in binding to the PAF receptor.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

Zawawi MS, Dharmapatni AA, Cantley MD, McHugh KP, Haynes DR, Crotti TN

Biochem Biophys Res Commun, 2012 Oct 19;427(2):404-9.
PMID: 23000414 DOI: 10.1016/j.bbrc.2012.09.077

Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p<0.05) reduced the expression of NFATc1, CathK, OSCAR, FcRγ, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p<0.05) decreased CathK, OSCAR, FcRγ, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.

Matched MeSH terms: Receptors, Cell Surface/metabolism*
Generation of mesenchymal stem cell from human umbilical cord tissue using a combination enzymatic and mechanical disassociation method

Tong CK, Vellasamy S, Tan BC, Abdullah M, Vidyadaran S, Seow HF, et al.

Cell Biol Int, 2011 Mar;35(3):221-6.
PMID: 20946106 DOI: 10.1042/CBI20100326

MSCs (mesenchymal stem cells) promise a great potential for regenerative medicine due to their unique properties of self-renewal, high plasticity, modulation of immune response and the flexibility for genetic modification. Therefore, the increasing demand for cellular therapy necessitates a larger-scale production of MSC; however, the technical and ethical issues had put a halt on it. To date, studies have shown that MSC could be derived from human UC (umbilical cord), which is once considered as clinical waste. We have compared the two conventional methods which are classic enzymatic digestion and explant method with our newly tailored enzymatic-mechanical disassociation method to generate UC-MSC. The generated UC-MSCs from the methods above were characterized based on their immunophenotyping, early embryonic transcription factors expression and mesodermal differentiation ability. Our results show that enzymatic-mechanical disassociation method increase the initial nucleated cell yield greatly (approximately 160-fold) and maximized the successful rate of UC-MSC generation. Enzymatic-mechanical disassociation-derived UC-MSC exhibited fibroblastic morphology and surface markers expression of CD105, CD73, CD29, CD90 and MHC class I. Furthermore, these cells constitutively express early embryonic transcription factors (Nanog, Oct-4, Sox-2 and Rex-1), as confirmed by RT-PCR, indicating their multipotency and high self-renewal capacity. They are also capable of differentiating into osteoblasts and adipocytes when given an appropriate induction. The present study demonstrates a new and efficient approach in generating MSC from UC, hence serving as ideal alternative source of mesenchymal stem cell for clinical and research use.

Matched MeSH terms: Receptors, Cell Surface/metabolism
Fulltext Effect of O-linked glycosylation on the antigenicity, cellular uptake and trafficking in dendritic cells of recombinant Ber e 1

Jambari NN, Liddell S, Martinez-Pomares L, Alcocer MJC

PLoS One, 2021;16(4):e0249876.
PMID: 33914740 DOI: 10.1371/journal.pone.0249876

Ber e 1, a major Brazil nut allergen, has been successfully produced in the yeast Pichia pastoris expression system as homogenous recombinant Ber e 1 (rBer e 1) with similar physicochemical properties and identical immunoreactivity to its native counterpart, nBer e 1. However, O-linked glycans was detected on the P.pastoris-derived rBer e 1, which is not naturally present in nBer e 1, and may contribute to the allergic sensitisation. In this study, we addressed the glycosylation differences between P. pastoris-derived recombinant Ber e 1 and its native counterparts. We also determined whether this fungal glycosylation could affect the antigenicity and immunogenicity of the rBer e 1 by using dendritic cells (DC) as an immune cell model due to their role in modulating the immune response. We identified that the glycosylation occurs at Ser96, Ser101 and Ser110 on the large chain and Ser19 on the small polypeptide chain of rBer e 1 only. The glycosylation on rBer e 1 was shown to elicit varying degree of antigenicity by binding to different combination of human leukocyte antigens (HLA) at different frequencies compared to nBer e 1 when tested using human DC-T cell assay. However, both forms of Ber e 1 are weak immunogens based from their low response indexes (RI). Glycans present on rBer e 1 were shown to increase the efficiency of the protein recognition and internalization by murine bone marrow-derived dendritic cells (bmDC) via C-type lectin receptors, particularly the mannose receptor (MR), compared to the non-glycosylated nBer e 1 and SFA8, a weak allergenic 2S albumin protein from sunflower seed. Binding of glycosylated rBer e 1 to MR alone was found to not induce the production of IL-10 that modulates bmDC to polarise Th2 cell response by suppressing IL-12 production and DC maturation. Our findings suggest that the O-linked glycosylation by P. pastoris has a small but measurable effect on the in vitro antigenicity of the rBer e 1 compared to its non-glycosylated counterpart, nBer e 1, and thus may influence its applications in diagnostics and immunotherapy.

Matched MeSH terms: Receptors, Cell Surface/metabolism

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