Author(s)

RuiMing Fan¹, Wei Bu², Yu Wei², LiLi Wu², YuanWen Liu², Lei Gong^3*

Affiliation(s)

¹Cerebrovascular Department, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China.

²Pharmacy Department, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China.

³Guizhou Engineering Research Center for Translational Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China.

Corresponding Author

Lei Gong

ABSTRACT

Objective: To explore the role of OPN in hyperglycemia with cerebral hemorrhage and neuroinflammatory injury and its preliminary mechanism. Methods: BV2 cells/RAW264.7 macrophages were stimulated with 30 ng/mL OPN for 24 hours in advance, and then cultured with 33 mmol/L high glucose medium for 24 hours. The expression of IL-1 β and iNOS in RAW264.7 cells was detected by RT-PCR, and the expression of TNF - α in BV2 cells was detected by Western blotting. The hyperglycemia model of rats after ICH (ICH+HG) was constructed, and the intervention was performed with anti OPN monoclonal antibody (0.4 mg/kg) and intraperitoneal injection of endoplasmic reticulum stress inhibitor (TUDC) (200 mg/kg). After administration, the neurological function score and HE staining of intracerebral hemorrhage tissues were performed, and the secretion levels of iNOS and TNF - α in intracerebral hemorrhage tissues were detected by ELISA. Results: In RAW264.7 cells, high glucose culture significantly increased the expression levels of iNOS and IL-1 β. Compared with high glucose group, OPN further increased the expression levels of iNOS and IL-1 β. In BV2 cells, high glucose culture significantly increased the expression of IL-1 β and TNF - α. Compared with high glucose group, OPN further increased the expression of IL-1 β and TNF - α. The neurological function score of rats in ICH+HG group increased significantly. Compared with the model group, the neurological function scores of rats in OPN monoclonal antibody group and TUDC group decreased. Conclusion: OPN can promote hyperglycemia associated with cerebral hemorrhage by inducing microglia and macrophage inflammation.

KEYWORDS

Bone bridging proteins; Hyperglycemia; Cerebral hemorrhage; Neuroinflammation

CITE THIS PAPER

RuiMing Fan, Wei Bu, Yu Wei, LiLi Wu, YuanWen Liu, Lei Gong. OPN promotes hyperglycemia with cerebral hemorrhage and neuroinflammatory injury by inducing microglia and macrophage inflammation. Eurasia Journal of Science and Technology. 2024, 6(3): 65-71. DOI: 10.61784/ejst3017.

REFERENCES

[1] Wang Y, Li K, Liu Z, et al. Ethyl Pyruvate Alleviating Inflammatory Response after Diabetic Cerebral Hemorrhage. Curr Neurovasc Res, 2022, 19(2): 196-202.

[2] Diener HC, Hankey GJ. Primary and Secondary Prevention of Ischemic Stroke and Cerebral Hemorrhage: JACC Focus Seminar. J Am Coll Cardiol, 2020, 75(15): 1804-1818.

[3] Chen S, Wan Y, Guo H, et al. Diabetic and stress-induced hyperglycemia in spontaneous intracerebral hemorrhage: A multicenter prospective cohort (CHEERY) study. CNS Neurosci Ther, 2023, 29(4): 979-987.

[4] Sun S, Pan Y, Zhao X, Liu L, Li H, He Y, et al. Prognostic Value of Admission Blood Glucose in Diabetic and Non-diabetic Patients with Intracerebral Hemorrhage. Sci Rep, 2016, 6: 32342.

[5] Chang JJ, Khorchid Y, Kerro A, et al. Sulfonylurea drug pretreatment and functional outcome in diabetic patients with acute intracerebral hemorrhage. J Neurol Sci, 2017, 381: 182-187.

[6] Yang S, Liu Y, Wang S, et al. Association between high serum blood glucose lymphocyte ratio and all-cause mortality in non-traumatic cerebral hemorrhage: a retrospective analysis of the MIMIC-IV database. Front Endocrinol (Lausanne), 2023, 14: 1290176.

[7] Ding H, Jia Y, Lv H, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells alleviate neuroinflammation after diabetic intracerebral hemorrhage via the miR-183-5p/PDCD4/NLRP3 pathway. J Endocrinol Invest, 2021, 44(12): 2685-2698.

[8] Subhramanyam C S, Wang C, Hu Q, Dheen S T Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol, 2019, 94: 112-120.

[9] Voet S, Prinz M, Van Loo G. Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. Trends Mol Med, 2019, 25(2): 112-123.

[10] De Vlaminck K, Van Hove H, Kancheva D, et al. Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation. Immunity, 2022, 55(11): 2085-2102 e2089.

[11] Hegdekar N, Sarkar C, Bustos S, et al. Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes. Autophagy 2023, 19(7): 2026-2044.

[12] Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem, 2018, 59: 17-24.

[13] Fortis S, Khadaroo RG, Haitsma JJ, et al. Osteopontin is associated with inflammation and mortality in a mouse model of polymicrobial sepsis. Acta Anaesthesiol Scand, 2015, 59(2): 170-175.

[14] Fu H, Liu X, Shi L, et al. Regulatory roles of Osteopontin in lung epithelial inflammation and epithelial-telocyte interaction. Clin Transl Med, 2023, 13(8): e1381.

[15] Manaenko A, Yang P, Nowrangi D, et al. Inhibition of stress fiber formation preserves blood-brain barrier after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab, 2018, 38(1): 87-102.

[16] Kashfi K, Kannikal J, Nath N. Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO. Cells, 2021, 10(11).

[17] Zhu L, Zhao Q, Yang T, et al. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2015, 34(1): 82-100.

[18] Xia Y, He F, Wu X, et al. GABA transporter sustains IL-1beta production in macrophages. Sci Adv, 2021, 7(15).

[19] Hirano S, Zhou Q, Furuyama A, Kanno S. Differential Regulation of IL-1beta and IL-6 Release in Murine Macrophages. Inflammation, 2017, 40(6): 1933-1943.

[20] McNeill E, Crabtree MJ, Sahgal N, et al. Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free Radic Biol Med, 2015, 79: 206-216.

[21] Bosca L, Zeini M, Traves PG, Hortelano S. Nitric oxide and cell viability in inflammatory cells: a role for NO in macrophage function and fate. Toxicology, 2005, 208(2): 249-258.

[22] Hua KF, Wang SH., Dong WC., Lin CY, Ho CL, Wu TH. High glucose increases nitric oxide generation in lipopolysaccharide-activated macrophages by enhancing activity of protein kinase C-alpha/delta and NF-kappaB. Inflamm Res, 2012, 61(10): 1107-1116.

[23] Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation, 2021, 18(1): 258.

[24] Liu X, Wang Y, Zeng Y, et al. Microglia-neuron interactions promote chronic itch via the NLRP3-IL-1beta-GRPR axis. Allergy, 2023, 78(6): 1570-1584.

[25] Lopez-Rodriguez AB, Hennessy E, Murray CL, et al. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1beta drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement, 2021, 17(10): 1735-1755.

[26] Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, et al. The Role of Tumor Necrosis Factor Alpha (TNF-alpha) in Autoimmune Disease and Current TNF-alpha Inhibitors in Therapeutics. Int J Mol Sci, 2021, 22(5).

[27] Bras JP, Bravo J, Freitas J, Barbosa MA, et al. TNF-alpha-induced microglia activation requires miR-342: impact on NF-kB signaling and neurotoxicity. Cell Death Dis, 2020, 11(6): 415.

[28] Wang H, Chen Y, Liu X, et al. TNF-alpha derived from arsenite-induced microglia activation mediated neuronal necroptosis. Ecotoxicol Environ Saf, 2022, 236: 113468.

[29] Zhang J, Li L, Xiu F. Sesamin suppresses high glucose-induced microglial inflammation in the retina in vitro and in vivo. J Neurophysiol, 2022, 127(2): 405-411.

[30] Chen X, Shi C, He M, et al. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther, 2023, 8(1): 352.