Microglial NLRP3 inflammasome activation-mediated inflammation promotes prolactinoma development

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China
  • 2 Department of Pharmacy, Tongren hospital affiliated to Wuhan University (the third hospital of Wuhan), Wuhan, China
  • 3 College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
  • 4 Department of Pathology, the central hospital of Wuhan, Tongji medical college, Huazhong University of Science and Technology, Wuhan, China

Correspondence should be addressed to X Guo: guoxl@sdu.edu.cn
Restricted access

Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3−/− mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 61 61 61
Full Text Views 3 3 3
PDF Downloads 5 5 5
  • Aflorei ED & Korbonits M 2014 Epidemiology and etiopathogenesis of pituitary adenomas. Journal of Neuro-Oncology 117 379394. (https://doi.org/10.1007/s11060-013-1354-5)

    • Search Google Scholar
    • Export Citation
  • Aguzzi A, Barres BA & Bennett ML 2013 Microglia: scapegoat, saboteur, or something else? Science 339 156161. (https://doi.org/10.1126/science.1227901)

    • Search Google Scholar
    • Export Citation
  • Arlicot N, Vercouillie J, Ribeiro MJ, Tauber C, Venel Y, Baulieu JL, Maia S, Corcia P, Stabin MG, Reynolds A, et al. 2012 Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation. Nuclear Medicine and Biology 39 570578. (https://doi.org/10.1016/j.nucmedbio.2011.10.012)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Kelly MA, Grandy DK & Low MJ 1999 Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology 140 53485355. (https://doi.org/10.1210/endo.140.11.7118)

    • Search Google Scholar
    • Export Citation
  • Bai M, Rone MB, Papadopoulos V & Bornhop DJ 2007 A novel functional translocator protein ligand for cancer imaging. Bioconjugate Chemistry 18 20182023. (https://doi.org/10.1021/bc700251e)

    • Search Google Scholar
    • Export Citation
  • Ben-Jonathan N & Hnasko R 2001 Dopamine as a prolactin (PRL) inhibitor. Endocrine Reviews 22 724763. (https://doi.org/10.1210/edrv.22.6.0451)

    • Search Google Scholar
    • Export Citation
  • Berraondo P, Minute L, Ajona D, Corrales L, Melero I & Pio R 2016 Innate immune mediators in cancer: between defense and resistance. Immunological Reviews 274 290306. (https://doi.org/10.1111/imr.12464)

    • Search Google Scholar
    • Export Citation
  • Canat X, Carayon P, Bouaboula M, Cahard D, Shire D, Roque C, Le Fur G & Casellas P 1993 Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells. Life Sciences 52 107118. (https://doi.org/10.1016/0024-3205(9390293-c)

    • Search Google Scholar
    • Export Citation
  • Cassel SL, Joly S & Sutterwala FS 2009 The NLRP3 inflammasome: a sensor of immune danger signals. Seminars in Immunology 21 194198. (https://doi.org/10.1016/j.smim.2009.05.002)

    • Search Google Scholar
    • Export Citation
  • Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M & Tavitian B 2009 Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. Journal of Nuclear Medicine 50 468476. (https://doi.org/10.2967/jnumed.108.058669)

    • Search Google Scholar
    • Export Citation
  • Chen L.C., Wang LJ, Tsang NM, Ojcius DM, Chen CC, Ouyang CN, Hsueh C, Liang Y, Chang KP, Chen CC, et al.2012 Tumour inflammasome-derived IL-1beta recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma. EMBO Molecular Medicine 4 1276-–1293. (https://doi.org/10.1002/emmm.201201569)

    • Search Google Scholar
    • Export Citation
  • Chen MK, Baidoo K, Verina T & Guilarte TR 2004 Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain 127 13791392. (https://doi.org/10.1093/brain/awh161)

    • Search Google Scholar
    • Export Citation
  • Chen MK & Guilarte TR 2008 Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacology and Therapeutics 118 117. (https://doi.org/10.1016/j.pharmthera.2007.12.004)

    • Search Google Scholar
    • Export Citation
  • Ciccarelli A, Daly AF & Beckers A 2005 The epidemiology of prolactinomas. Pituitary 8 36. (https://doi.org/10.1007/s11102-005-5079-0)

  • Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, et al.2015 A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine 21 248255. (https://doi.org/10.1038/nm.3806)

    • Search Google Scholar
    • Export Citation
  • Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez AI, Martinez CM, Angosto D, Montero MT, Herranz AS, Bazan E, Reimers D, et al.2012 2012 cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37 487500. (https://doi.org/10.1016/j.immuni.2012.06.013)

    • Search Google Scholar
    • Export Citation
  • de Visser KE, Eichten A & Coussens LM 2006 Paradoxical roles of the immune system during cancer development. Nature Reviews: Cancer 6 2437. (https://doi.org/10.1038/nrc1782)

    • Search Google Scholar
    • Export Citation
  • Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, et al.2010 NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 13571361. (https://doi.org/10.1038/nature08938)

    • Search Google Scholar
    • Export Citation
  • Farrell WE 2006 Pituitary tumours: findings from whole genome analyses. Endocrine-Related Cancer 13 707716. (https://doi.org/10.1677/erc.1.01131)

    • Search Google Scholar
    • Export Citation
  • Grivennikov SI, Greten FR & Karin M 2010 Immunity, inflammation, and cancer. Cell 140 883899. (https://doi.org/10.1016/j.cell.2010.01.025)

  • Hanahan D & Weinberg RA 2011 Hallmarks of cancer: the next generation. Cell 144 646674. (https://doi.org/10.1016/j.cell.2011.02.013)

  • Hanisch UK & Kettenmann H 2007 Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10 13871394. (https://doi.org/10.1038/nn1997)

    • Search Google Scholar
    • Export Citation
  • Heaney AP, Horwitz GA, Wang Z, Singson R & Melmed S 1999 Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nature Medicine 5 13171321. (https://doi.org/10.1038/15275)

    • Search Google Scholar
    • Export Citation
  • Hussain SP & Harris CC 2007 Inflammation and cancer: an ancient link with novel potentials. International Journal of Cancer 121 23732380. (https://doi.org/10.1002/ijc.23173)

    • Search Google Scholar
    • Export Citation
  • Jayakumar AR, Panickar KS & Norenberg MD 2002 Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. Journal of Neurochemistry 83 12261234. (https://doi.org/10.1046/j.1471-4159.2002.01261.x)

    • Search Google Scholar
    • Export Citation
  • Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q, et al.2017 Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. Journal of Experimental Medicine 214 32193238. (https://doi.org/10.1084/jem.20171419)

    • Search Google Scholar
    • Export Citation
  • Jorda EG, Jimenez A, Verdaguer E, Canudas AM, Folch J, Sureda FX, Camins A & Pallas M 2005 Evidence in favour of a role for peripheral-type benzodiazepine receptor ligands in amplification of neuronal apoptosis. Apoptosis 10 91104. (https://doi.org/10.1007/s10495-005-6064-9)

    • Search Google Scholar
    • Export Citation
  • Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N, Grandy DK, et al.1997 Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19 103113. (https://doi.org/10.1016/s0896-6273(0080351-7)

    • Search Google Scholar
    • Export Citation
  • Kovats S 2015 Estrogen receptors regulate innate immune cells and signaling pathways. Cellular Immunology 294 6369. (https://doi.org/10.1016/j.cellimm.2015.01.018)

    • Search Google Scholar
    • Export Citation
  • Li L & Liu Y 2015 Aging-related gene signature regulated by Nlrp3 predicts glioma progression. American Journal of Cancer Research 5 442449.

    • Search Google Scholar
    • Export Citation
  • Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, Kassiou M, Dolle F & Tavitian B 2010 Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism 30 230241. (https://doi.org/10.1038/jcbfm.2009.205)

    • Search Google Scholar
    • Export Citation
  • Martinon F, Petrilli V, Mayor A, Tardivel A & Tschopp J 2006 Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440 237241. (https://doi.org/10.1038/nature04516)

    • Search Google Scholar
    • Export Citation
  • McAllister SS & Weinberg RA 2010 Tumor-host interactions: a far-reaching relationship. Journal of Clinical Oncology 28 40224028. (https://doi.org/10.1200/JCO.2010.28.4257)

    • Search Google Scholar
    • Export Citation
  • Melmed S 2015 Pituitary tumors. Endocrinology and Metabolism Clinics of North America 44 19. (https://doi.org/10.1016/j.ecl.2014.11.004)

    • Search Google Scholar
    • Export Citation
  • Ntali G & Wass JA 2018 Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas. Pituitary 21 111118. (https://doi.org/10.1007/s11102-018-0869-3)

    • Search Google Scholar
    • Export Citation
  • Pineros M, Sierra MS, Izarzugaza MI & Forman D 2016 Descriptive epidemiology of brain and central nervous system cancers in Central and South America. Cancer Epidemiology 44(Supplement 1) S141S149. (https://doi.org/10.1016/j.canep.2016.04.007)

    • Search Google Scholar
    • Export Citation
  • Prinz M, Erny D & Hagemeyer N 2017 Ontogeny and homeostasis of CNS myeloid cells. Nature Immunology 18 385392. (https://doi.org/10.1038/ni.3703)

    • Search Google Scholar
    • Export Citation
  • Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, Llop J, Gomez V, Gispert JD, Millan O, et al.2007 Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. Journal of Cerebral Blood Flow and Metabolism 27 19751986. (https://doi.org/10.1038/sj.jcbfm.9600500)

    • Search Google Scholar
    • Export Citation
  • Ruff MR, Pert CB, Weber RJ, Wahl LM, Wahl SM & Paul SM 1985 Benzodiazepine receptor-mediated chemotaxis of human monocytes. Science 229 12811283. (https://doi.org/10.1126/science.2994216)

    • Search Google Scholar
    • Export Citation
  • Schroder K & Tschopp J 2010 The inflammasomes. Cell 140 821832. (https://doi.org/10.1016/j.cell.2010.01.040)

  • Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, Zhou QB, Huang YY, Liu YJ, Wawrousek E, et al.2013 Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature 494 9094. (https://doi.org/10.1038/nature11748)

    • Search Google Scholar
    • Export Citation
  • Tarassishin L, Casper D & Lee SC 2014 Aberrant expression of interleukin-1beta and inflammasome activation in human malignant gliomas. PLoS ONE 9 e103432. (https://doi.org/10.1371/journal.pone.0103432)

    • Search Google Scholar
    • Export Citation
  • Villa A, Vegeto E, Poletti A & Maggi A 2016 Estrogens, neuroinflammation, and neurodegeneration. Endocrine Reviews 37 372402 (https://doi.org/10.1210/er.2016-1007)

    • Search Google Scholar
    • Export Citation
  • Vlodavsky E & Soustiel JF 2007 Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. Journal of Neuro-Oncology 81 17. (https://doi.org/10.1007/s11060-006-9199-9)

    • Search Google Scholar
    • Export Citation
  • Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, Borson-Chazot F, Naves LA, Brue T, Gatta B, et al.2012 Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. European Journal of Endocrinology 167 651662. (https://doi.org/10.1530/EJE-12-0236)

    • Search Google Scholar
    • Export Citation
  • Waller R, Baxter L, Fillingham DJ, Coelho S, Pozo JM, Mozumder M, Frangi AF, Ince PG & Simpson JE Highley JR Jr 2019 Iba-1-/CD68+ microglia are a prominent feature of age-associated deep subcortical white matter lesions. PLoS ONE 14 e0210888. (https://doi.org/10.1371/journal.pone.0210888)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Yue X, Kiesewetter DO, Niu G, Teng G & Chen X 2014a PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. European Journal of Nuclear Medicine and Molecular Imaging 41 14401449. (https://doi.org/10.1007/s00259-014-2727-5)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Yue X, Kiesewetter DO, Wang Z, Lu J, Niu G, Teng G & Chen X 2014b [(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke. Molecular Pharmaceutics 11 34633470. (https://doi.org/10.1021/mp500234d)

    • Search Google Scholar
    • Export Citation
  • Wong A, Eloy JA, Couldwell WT & Liu JK 2015a Update on prolactinomas. Part 1: Clinical manifestations and diagnostic challenges. Journal of Clinical Neuroscience 22 15621567. (https://doi.org/10.1016/j.jocn.2015.03.058)

    • Search Google Scholar
    • Export Citation
  • Wong A, Eloy JA, Couldwell WT & Liu JK 2015b Update on prolactinomas. Part 2: Treatment and management strategies. Journal of Clinical Neuroscience 22 15681574 (https://doi.org/10.1016/j.jocn.2015.03.059)

    • Search Google Scholar
    • Export Citation
  • Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z & Zhou R 2015 Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160 6273. (https://doi.org/10.1016/j.cell.2014.11.047)

    • Search Google Scholar
    • Export Citation
  • Yui J, Maeda J, Kumata K, Kawamura K, Yanamoto K, Hatori A, Yamasaki T, Nengaki N, Higuchi M & Zhang MR 2010 18F-FEAC and 18F-FEDAC: PET of the monkey brain and imaging of translocator protein (18 kDa) in the infarcted rat brain. Journal of Nuclear Medicine 51 13011309. (https://doi.org/10.2967/jnumed.109.072223)

    • Search Google Scholar
    • Export Citation
  • Zhu J, Hu Z, Han X, Wang D, Jiang Q, Ding J, Xiao M, Wang C, Lu M & Hu G 2018 Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of beta-arrestin2 and NLRP3. Cell Death and Differentiation 25 20372049. (https://doi.org/10.1038/s41418-018-0127-2)

    • Search Google Scholar
    • Export Citation