Differential changes in Neuregulin-1 signaling in major brain regions in a lipopolysaccharide-induced neuroinflammation mouse model

Yang,Zhai; Jiang,Qiong; Chen,Shuang‑Xi; Hu,Cheng‑Liang; Shen,Hui‑Fan; Huang,Pei‑Zhi; Xu,Jun‑Ping; Mei,Jin‑Ping; Zhang,Ben‑Ping; Zhao,Wei‑Jiang

doi:10.3892/mmr.2016.5325

Differential changes in Neuregulin-1 signaling in major brain regions in a lipopolysaccharide-induced neuroinflammation mouse model

Authors:
- Zhai Yang
- Qiong Jiang
- Shuang‑Xi Chen
- Cheng‑Liang Hu
- Hui‑Fan Shen
- Pei‑Zhi Huang
- Jun‑Ping Xu
- Jin‑Ping Mei
- Ben‑Ping Zhang
- Wei‑Jiang Zhao
View Affiliations

Affiliations: Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China, Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China, Department of Neurology, The 2nd Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
Published online on: May 23, 2016 https://doi.org/10.3892/mmr.2016.5325
Pages: 790-796
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Neuregulin 1 (Nrg1) is involved in multiple biological processes in the nervous system. The present study investigated changes in Nrg1 signaling in the major brain regions of mice subjected to lipopolysaccharide (LPS)-induced neuroinflammation. At 24 h post‑intraperitoneal injection of LPS, mouse brain tissues, including tissues from the cortex, striatum, hippocampus and hypothalamus, were collected. Reverse transcription‑polymerase chain reaction was used to determine the expression of Nrg1 and its receptors, Neu and ErbB4, at the mRNA level. Western blotting was performed to determine the levels of these proteins and the protein levels of phosphorylated extracellular signal-regulated kinases (Erk)1/2 and Akt1. Immunohistochemical staining was utilized to detect the levels of pNeu and pErbB4 in these regions. LPS successfully induced sites of neuroinflammation in these regions, in which changes in Nrg1, Neu and ErbB4 at the mRNA and protein levels were identified compared with controls. LPS induced a reduction in pNeu and pErbB4 in the striatum and hypothalamus, although marginally increased pErbB4 levels were found in the hippocampus. LPS increased the overall phosphorylation of Src but this effect was reduced in the hypothalamus. Moreover, increased phosphorylation of Akt1 was found in the striatum and hippocampus. These data suggest diverse roles for Nrg1 signaling in these regions during the process of neuroinflammation.

View Figures

View References

1	Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, Neiswender H, Dong XP, Wu J, Gassmann M, et al: Neuregulin-1 enhances depolarization-induced GABA release. Neuron. 54:599–610. 2007. View Article : Google Scholar : PubMed/NCBI
2	Hancock ML, Canetta SE, Role LW and Talmage DA: Presynaptic type III neuregulin1-ErbB signaling targets alpha7 nicotinic acetylcholine receptors to axons. J Gen Physiol. 131:i42008. View Article : Google Scholar : PubMed/NCBI
3	Liu J and Kern JA: Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol. 27:306–313. 2002. View Article : Google Scholar : PubMed/NCBI
4	Shamir A and Buonanno A: Molecular and cellular characterization of Neuregulin-1 type IV isoforms. J Neurochem. 113:1163–1176. 2010.PubMed/NCBI
5	Shyu WC, Lin SZ, Chiang MF, Yang HI, Thajeb P and Li H: Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging. 25:935–944. 2004. View Article : Google Scholar : PubMed/NCBI
6	Zhao W and Ren SG: Neuregulin-1 (Nrg1) is mainly expressed in rat pituitary gonadotroph cells and possibly regulates prolactin (PRL) secretion in a juxtacrine manner. J Neuroendocrinol. 23:1252–1262. 2011. View Article : Google Scholar : PubMed/NCBI
7	Zhao W, Shen Y and Ren S: Endogenous expression of Neuregulin-1 (Nrg1) as a potential modulator of prolactin (PRL) secretion in GH3 cells. Cell Tissue Res. 344:313–320. 2011. View Article : Google Scholar : PubMed/NCBI
8	Zhao WJ and Ren SG: Endogenous neuregulin-1 expression in the anterior pituitary of female Wistar-Furth rats during the estrous cycle. Nan Fang Yi Ke Da Xue Xue Bao. 31:921–927. 2011.In Chinese. PubMed/NCBI
9	Peles E, Ben-Levy R, Tzahar E, Liu N, Wen D and Yarden Y: Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. EMBO J. 12:961–971. 1993.PubMed/NCBI
10	Puricelli L, Proietti CJ, Labriola L, Salatino M, Balañá ME, Aguirre Ghiso J, Lupu R, Pignataro OP, Charreau EH, Bal de Kier Joffé E and Elizalde PV: Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. Int J Cancer. 100:642–653. 2002. View Article : Google Scholar : PubMed/NCBI
11	Rebola N, Simões AP, Canas PM, Tomó AR, Andrade GM, Barry CE, Agostinho PM, Lynch MA and Cunha RA: Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J Neurochem. 117:100–111. 2011. View Article : Google Scholar : PubMed/NCBI
12	Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN and Carroll SL: Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J Neuropathol Exp Neurol. 62:42–54. 2003. View Article : Google Scholar : PubMed/NCBI
13	Viehover A, Miller RH, Park SK, Fischbach G and Vartanian T: Neuregulin: An oligodendrocyte growth factor absent in active multiple sclerosis lesions. Dev Neurosci. 23:377–386. 2001. View Article : Google Scholar
14	Corfas G, Roy K and Buxbaum JD: Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci. 7:575–580. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ritch PA, Carroll SL and Sontheimer H: Neuregulin-1 enhances motility and migration of human astrocytic glioma cells. J Biol Chem. 278:20971–20978. 2003. View Article : Google Scholar : PubMed/NCBI
16	Hirsch EC and Hunot S: Neuroinflammation in Parkinson's disease: A target for neuroprotection? Lancet Neurol. 8:382–397. 2009. View Article : Google Scholar : PubMed/NCBI
17	Gaillard PJ, de Boer AB and Breimer DD: Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro. Microvasc Res. 65:24–31. 2003. View Article : Google Scholar : PubMed/NCBI
18	Glezer I, Simard AR and Rivest S: Neuroprotective role of the innate immune system by microglia. Neuroscience. 147:867–883. 2007. View Article : Google Scholar : PubMed/NCBI
19	Nawa H and Takei N: Recent progress in animal modeling of immune inflammatory processes in schizophrenia: Implication of specific cytokines. Neurosci Res. 56:2–13. 2006. View Article : Google Scholar : PubMed/NCBI
20	Hoffmann I, Bueter W, Zscheppang K, Brinkhaus MJ, Liese A, Riemke S, Dörk T, Dammann O and Dammann CE: Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns. Brain Behav Immun. 24:784–791. 2010. View Article : Google Scholar :
21	Cao M, Zheng H, Tan X, Xu W, Rui Y, Li L, Liu X, Xu G, Cui G, Xu J, et al: Upregulation of CBLL1 in rat brain cortex after lipopolysaccharide treated. J Mol Histol. 44:135–145. 2013. View Article : Google Scholar
22	Chiu K, Lau WM, Lau HT, So KF and Chang RC: Micro-dissection of rat brain for RNA or protein extraction from specific brain region. J Vis Exp. 269:2007.
23	Dreymueller D, Martin C, Schumacher J, Groth E, Boehm JK, Reiss LK, Uhlig S and Ludwig A: Smooth muscle cells relay acute pulmonary inflammation via distinct ADAM17/ErbB axes. J Immunol. 192:722–731. 2014. View Article : Google Scholar
24	Zhu L, Bi W and Lu D, Zhang C, Shu X, Wang H, Qi R, Shi Q and Lu D: Regulation of ubiquitin-specific processing protease 8 suppresses neuroinflammation. Mol Cell Neurosci. 64:74–83. 2015. View Article : Google Scholar
25	Xu Z, Jiang J, Ford G and Ford BD: Neuregulin-1 is neuro-protective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun. 322:440–446. 2004. View Article : Google Scholar : PubMed/NCBI
26	Bermingham-McDonogh O, McCabe KL and Reh TA: Effects of GGF/neuregulins on neuronal survival and neurite outgrowth correlate with erbB2/neu expression in developing rat retina. Development. 122:1427–1438. 1996.PubMed/NCBI
27	Verdi JM, Groves AK, Farinas I, Jones K, Marchionni MA, Reichardt LF and Anderson DJ: A reciprocal cell-cell interaction mediated by NT-3 and neuregulins controls the early survival and development of sympathetic neuroblasts. Neuron. 16:515–527. 1996. View Article : Google Scholar : PubMed/NCBI
28	Vaskovsky A, Lupowitz Z, Erlich S and Pinkas-Kramarski R: ErbB-4 activation promotes neurite outgrowth in PC12 cells. J Neurochem. 74:979–987. 2000. View Article : Google Scholar : PubMed/NCBI
29	Erlich S, Goldshmit Y, Lupowitz Z and Pinkas-Kramarski R: ErbB-4 activation inhibits apoptosis in PC12 cells. Neuroscience. 107:353–362. 2001. View Article : Google Scholar : PubMed/NCBI
30	Goldshmit Y, Erlich S and Pinkas-Kramarski R: Neuregulin rescues PC12-ErbB4 cells from cell death induced by H₂O₂. Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase. J Biol Chem. 276:46379–46385. 2001. View Article : Google Scholar : PubMed/NCBI
31	Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, et al: Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 362:312–318. 1993. View Article : Google Scholar : PubMed/NCBI
32	Pinkas-Kramarski R, Eilam R, Spiegler O, Lavi S, Liu N, Chang D, Wen D, Schwartz M and Yarden Y: Brain neurons and glial cells express Neu differentiation factor/heregulin: A survival factor for astrocytes. Proc Natl Acad Sci USA. 91:9387–9391. 1994. View Article : Google Scholar : PubMed/NCBI
33	Pinkas-Kramarski R, Eilam R, Alroy I, Levkowitz G, Lonai P and Yarden Y: Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene. 15:2803–2815. 1997. View Article : Google Scholar
34	Eilam R, Pinkas-Kramarski R, Ratzkin BJ, Segal M and Yarden Y: Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain. Proc Natl Acad Sci USA. 95:1888–1893. 1998. View Article : Google Scholar : PubMed/NCBI
35	Erlich S, Shohami E and Pinkas-Kramarski R: Closed head injury induces up-regulation of ErbB-4 receptor at the site of injury. Mol Cell Neurosci. 16:597–608. 2000. View Article : Google Scholar : PubMed/NCBI
36	Esper RM, Pankonin MS and Loeb JA: Neuregulins: Versatile growth and differentiation factors in nervous system development and human disease. Brain Res Rev. 51:161–175. 2006. View Article : Google Scholar : PubMed/NCBI
37	Ghosh S, May MJ and Kopp EB: NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 16:225–260. 1998. View Article : Google Scholar : PubMed/NCBI
38	Buonanno A and Fischbach GD: Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol. 11:287–296. 2001. View Article : Google Scholar : PubMed/NCBI
39	Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, Kulkarni AB and Pant HC: Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem. 278:35702–35709. 2003. View Article : Google Scholar : PubMed/NCBI