Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Inflammation Research
Erschienen in: Inflammation Research 6/2023

14.06.2023 | Original Research Paper

Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling

verfasst von: Jiwon Kim, A Young Sim, Sumit Barua, Jong Youl Kim, Jong Eun Lee

Erschienen in: Inflammation Research | Ausgabe 6/2023

Einloggen, um Zugang zu erhalten

Abstract

Background

Following central nervous system (CNS) injury, the investigation for neuroinflammation is vital because of its pleiotropic role in both acute injury and long-term recovery. Agmatine (Agm) is well known for its neuroprotective effects and anti-neuroinflammatory properties. However, Agm’s mechanism for neuroprotection is still unclear. We screened target proteins that bind to Agm using a protein microarray; the results showed that Agm strongly binds to interferon regulatory factor 2 binding protein (IRF2BP2), which partakes in the inflammatory response. Based on these prior data, we attempted to elucidate the mechanism by which the combination of Agm and IRF2BP2 induces a neuroprotective phenotype of microglia.

Methods

To confirm the relationship between Agm and IRF2BP2 in neuroinflammation, we used microglia cell-line (BV2) and treated with lipopolysaccharide from Escherichia coli 0111:B4 (LPS; 20 ng/mL, 24 h) and interleukin (IL)-4 (20 ng/mL, 24 h). Although Agm bound to IRF2BP2, it failed to enhance IRF2BP2 expression in BV2.
Therefore, we shifted our focus onto interferon regulatory factor 2 (IRF2), which is a transcription factor and interacts with IRF2BP2.

Results

IRF2 was highly expressed in BV2 after LPS treatment but not after IL-4 treatment. When Agm bound to IRF2BP2 following Agm treatment, the free IRF2 translocated to the nucleus of BV2. The translocated IRF2 activated the transcription of Kruppel-like factor 4 (KLF4), causing KLF4 to be induced in BV2. The expression of KLF4 increased the CD206-positive cells in BV2.

Conclusions

Taken together, unbound IRF2, resulting from the competitive binding of Agm to IRF2BP2, may provide neuroprotection against neuroinflammation via an anti-inflammatory mechanism of microglia involving the expression of KLF4.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zhu MY, Piletz JE, Halaris A, Regunathan S. Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells. Cell Mol Neurobiol. 2003;23:865–72.CrossRefPubMed
2.
Kim JH, Yenari MA, Giffard RG, Cho SW, Park KA, Lee JE. Agmatine reduces infarct area in a mouse model of transient focal cerebral ischemia and protects cultured neurons from ischemia-like injury. Exp Neurol. 2004;189:122–30.CrossRefPubMed
3.
Wang WP, Iyo AH, Miguel-Hidalgo J, Regunathan S, Zhu MY. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons. Brain Res. 2006;1084:210–6.PubMedCentralCrossRefPubMed
4.
Kim JH, Lee YW, Park KA, Lee WT, Lee JE. Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:943–9.CrossRefPubMed
5.
Yang MZ, Mun CH, Choi YJ, Baik JH, Park KA, Lee WT, et al. Agmatine inhibits matrix metalloproteinase-9 via endothelial nitric oxide synthase in cerebral endothelial cells. Neurol Res. 2007;29:749–54.CrossRefPubMed
6.
Lee WT, Hong S, Yoon SH, Kim JH, Park KA, Seong GJ, et al. Neuroprotective effects of agmatine on oxygen-glucose deprived primary-cultured astrocytes and nuclear translocation of nuclear factor-kappa B. Brain Res. 2009;1281:64–70.CrossRefPubMed
7.
Chen HH, Keyhanian K, Zhou X, Vilmundarson RO, Almontashiri NA, Cruz SA, et al. IRF2BP2 reduces macrophage inflammation and susceptibility to atherosclerosis. Circ Res. 2015;117:671–83.CrossRefPubMed
8.
9.
Cruz SA, Hari A, Qin Z, Couture P, Huang H, Lagace DC, et al. Loss of IRF2BP2 in microglia increases inflammation and functional deficits after focal ischemic brain injury. Front Cell Neurosci. 2017;11:201.PubMedCentralCrossRefPubMed
10.
Giulian D, Corpuz M, Chapman S, Mansouri M, Robertson C. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res. 1993;36:681–93.CrossRefPubMed
11.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 2003;100:8514–9.PubMedCentralCrossRefPubMed
12.
Huang WC, Qiao Y, Xu L, Kacimi R, Sun X, Giffard RG, et al. Direct protection of cultured neurons from ischemia-like injury by minocycline. Anat Cell Biol. 2010;43:325–31.PubMedCentralCrossRefPubMed
13.
Kawabori M, Yenari MA. The role of the microglia in acute CNS injury. Metab Brain Dis. 2015;30:381–92.CrossRefPubMed
14.
Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. 2011;11:775–87.CrossRefPubMed
15.
Kim JY, Kim N, Yenari MA. Mechanisms and potential therapeutic applications of microglial activation after brain injury. CNS Neurosci Ther. 2015;21:309–19.CrossRefPubMed
16.
Barua S, Sim AY, Kim JY, Shin I, Lee JE. Maintenance of the neuroprotective function of the amino group blocked fluorescence-agmatine. Neurochem Res. 2021;46:1933–40.PubMedCentralCrossRefPubMed
17.
Joshi L, Plastira I, Bernhart E, Reicher H, Triebl A, Kofeler HC, et al. Inhibition of autotaxin and lysophosphatidic acid receptor 5 attenuates neuroinflammation in LPS-activated BV-2 microglia and a mouse endotoxemia model. Int J Mol Sci. 2021;22:8519.PubMedCentralCrossRefPubMed
18.
Plastira I, Bernhart E, Goeritzer M, Reicher H, Kumble VB, Kogelnik N, et al. 1-Oleyl-lysophosphatidic acid (LPA) promotes polarization of BV-2 and primary murine microglia towards an M1-like phenotype. J Neuroinflammation. 2016;13:205.PubMedCentralCrossRefPubMed
19.
Ramalho-Oliveira R, Oliveira-Vieira B, Viola JPB. IRF2BP2: a new player in the regulation of cell homeostasis. J Leukoc Biol. 2019;106:717–23.CrossRefPubMed
20.
Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, Bobryshev YV. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2. Immunobiology. 2018;223:101–11.CrossRefPubMed
21.
Barber SA, Fultz MJ, Salkowski CA, Vogel SN. Differential expression of interferon regulatory factor 1 (IRF-1), IRF-2, and interferon consensus sequence binding protein genes in lipopolysaccharide (LPS)-responsive and LPS-hyporesponsive macrophages. Infect Immun. 1995;63:601–8.PubMedCentralCrossRefPubMed
22.
Harada H, Takahashi E, Itoh S, Harada K, Hori TA, Taniguchi T. Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Mol Cell Biol. 1994;14:1500–9.PubMedCentralPubMed
23.
Hayes MP, Zoon KC. Priming of human monocytes for enhanced lipopolysaccharide responses: expression of alpha interferon, interferon regulatory factors, and tumor necrosis factor. Infect Immun. 1993;61:3222–7.PubMedCentralCrossRefPubMed
24.
Cui H, Banerjee S, Guo S, Xie N, Liu G. IFN regulatory factor 2 inhibits expression of glycolytic genes and lipopolysaccharide-induced proinflammatory responses in macrophages. J Immunol. 2018;200:3218–30.CrossRefPubMed
25.
Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, et al. Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest. 2011;121:2736–49.PubMedCentralCrossRefPubMed
26.
Li Z, Martin M, Zhang J, Huang HY, Bai L, Zhang J, et al. Kruppel-like factor 4 regulation of cholesterol-25-hydroxylase and liver X receptor mitigates atherosclerosis susceptibility. Circulation. 2017;136:1315–30.PubMedCentralCrossRefPubMed
27.
Satriano J, Isome M, Casero RA Jr, Thomson SC, Blantz RC. Polyamine transport system mediates agmatine transport in mammalian cells. Am J Physiol Cell Physiol. 2001;281:C329–34.CrossRefPubMed
28.
Wang CC, Chio CC, Chang CH, Kuo JR, Chang CP. Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia. BMC Pharmacol. 2010;10:11.PubMedCentralCrossRefPubMed
29.
Freitas AE, Egea J, Buendia I, Navarro E, Rada P, Cuadrado A, et al. Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line. Mol Neurobiol. 2015;51:1504–19.CrossRefPubMed
30.
Chai J, Luo L, Hou F, Fan X, Yu J, Ma W, et al. Agmatine reduces lipopolysaccharide-mediated oxidant response via activating PI3K/Akt pathway and up-regulating Nrf2 and HO-1 expression in macrophages. PLoS ONE. 2016;11: e0163634.PubMedCentralCrossRefPubMed
31.
Sahin C, Albayrak O, Akdeniz TF, Akbulut Z, Yanikkaya Demirel G, Aricioglu F. Agmatine reverses sub-chronic stress induced nod-like receptor protein 3 (NLRP3) activation and cytokine response in rats. Basic Clin Pharmacol Toxicol. 2016;119:367–75.CrossRefPubMed
32.
Arruda LC, Lorenzi JC, Sousa AP, Zanette DL, Palma PV, Panepucci RA, et al. Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients. Bone Marrow Transplant. 2015;50:380–9.CrossRefPubMed
33.
Elser B, Lohoff M, Kock S, Giaisi M, Kirchhoff S, Krammer PH, et al. IFN-gamma represses IL-4 expression via IRF-1 and IRF-2. Immunity. 2002;17:703–12.CrossRefPubMed
34.
Xie C, Liu C, Wu B, Lin Y, Ma T, Xiong H, et al. Effects of IRF1 and IFN-beta interaction on the M1 polarization of macrophages and its antitumor function. Int J Mol Med. 2016;38:148–60.PubMedCentralCrossRefPubMed
35.
Zhang S, Thomas K, Blanco JC, Salkowski CA, Vogel SN. The role of the interferon regulatory factors, IRF-1 and IRF-2, in LPS-induced cyclooxygenase-2 (COX-2) expression in vivo and in vitro. J Endotoxin Res. 2002;8:379–88.CrossRefPubMed
36.
Klune JR, Dhupar R, Kimura S, Ueki S, Cardinal J, Nakao A, et al. Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2012;303:G666–73.PubMedCentralCrossRefPubMed
37.
Fehr T, Schoedon G, Odermatt B, Holtschke T, Schneemann M, Bachmann MF, et al. Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis. J Exp Med. 1997;185:921–31.PubMedCentralCrossRefPubMed
38.
Wei D, Kanai M, Huang S, Xie K. Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis. 2006;27:23–31.CrossRefPubMed
39.
Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 2006;6:11–23.CrossRefPubMed
40.
Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, et al. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J. 2007;26:4138–48.PubMedCentralCrossRefPubMed
41.
Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK. Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages. J Biol Chem. 2005;280:38247–58.CrossRefPubMed
42.
Li B, Sheng Z, Liu C, Qian L, Wu Y, Wu Y, et al. Kallistatin inhibits atherosclerotic inflammation by regulating macrophage polarization. Hum Gene Ther. 2019;30:339–51.CrossRefPubMed
43.
Sharma N, Lu Y, Zhou G, Liao X, Kapil P, Anand P, et al. Myeloid Kruppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice–brief report. Arterioscler Thromb Vasc Biol. 2012;32:2836–8.PubMedCentralCrossRefPubMed
Metadaten
Titel
Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling
verfasst von
Jiwon Kim
A Young Sim
Sumit Barua
Jong Youl Kim
Jong Eun Lee
Publikationsdatum
14.06.2023
Verlag
Springer International Publishing
Erschienen in
Inflammation Research / Ausgabe 6/2023
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-023-01741-z

Weitere Artikel der Ausgabe 6/2023

Inflammation Research 6/2023 Zur Ausgabe

Review

New small molecules in dermatology: for the autoimmunity, inflammation and beyond

Review

Dual role of ANGPTL4 in inflammation

Correction

Correction to: Fructose malabsorption in ChREBP-deficient mice disrupts the small intestine immune microenvironment and leads to diarrhea-dominant bowel habit changes

Original Research Paper

Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation

Review

From bench to bedside: targeting lymphocyte activation gene 3 as a therapeutic strategy for autoimmune diseases

Review

Neutrophil sub-types in maintaining immune homeostasis during steady state, infections and sterile inflammation

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

16.05.2024 alpha-1-Rezeptorantagonisten Nachrichten

Nach einer Prostatabiopsie treten häufig Probleme beim Wasserlassen auf. Ob sich das durch den periinterventionellen Einsatz von Alphablockern verhindern lässt, haben australische Mediziner im Zuge einer Metaanalyse untersucht.

Eingreifen von Umstehenden rettet vor Erstickungstod!

15.05.2024 Fremdkörperaspiration Nachrichten

Wer sich an einem Essensrest verschluckt und um Luft ringt, benötigt vor allem rasche Hilfe. Dass Umstehende nur in jedem zweiten Erstickungsnotfall bereit waren, diese zu leisten, ist das ernüchternde Ergebnis einer Beobachtungsstudie aus Japan. Doch es gibt auch eine gute Nachricht.

Neue S3-Leitlinie zur unkomplizierten Zystitis: Auf Antibiotika verzichten?

15.05.2024 Harnwegsinfektionen Nachrichten

Welche Antibiotika darf man bei unkomplizierter Zystitis verwenden und wovon sollte man die Finger lassen? Welche pflanzlichen Präparate können helfen? Was taugt der zugelassene Impfstoff? Antworten vom Koordinator der frisch überarbeiteten S3-Leitlinie, Prof. Florian Wagenlehner.

Schadet Ärger den Gefäßen?

14.05.2024 Arteriosklerose Nachrichten

In einer Studie aus New York wirkte sich Ärger kurzfristig deutlich negativ auf die Endothelfunktion gesunder Probanden aus. Möglicherweise hat dies Einfluss auf die kardiovaskuläre Gesundheit.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise