Plexin-A1 is required for Toll-like receptor‑mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy

Ito,Takuji; Yoshida,Kenji; Negishi,Takayuki; Miyajima,Masayasu; Takamatsu,Hyota; Kikutani,Hitoshi; Kumanogoh,Atsushi; Yukawa,Kazunori

doi:10.3892/ijmm.2014.1690

Plexin-A1 is required for Toll-like receptor‑mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy

Authors:
- Takuji Ito
- Kenji Yoshida
- Takayuki Negishi
- Masayasu Miyajima
- Hyota Takamatsu
- Hitoshi Kikutani
- Atsushi Kumanogoh
- Kazunori Yukawa
View Affiliations

Affiliations: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan, Laboratory Animal Center, Wakayama Medical University, Wakayama 641-8509, Japan, Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Published online on: March 7, 2014 https://doi.org/10.3892/ijmm.2014.1690
Pages: 1122-1130
Copyright: © Ito et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Recent investigations have suggested that semaphorins, which are known repulsive axon guidance molecules, may play a crucial role in maintaining brain homeostasis by regulating microglial activity. Sema3A, secreted in higher amounts from injured neurons, is considered to suppress excessive inflammatory responses by inducing microglial apoptosis through its binding to Plexin-A1 receptors on activated microglia. To clarify the in vivo role of Plexin-A1-mediated signaling in lipopolysaccharide (LPS)-induced injury in mouse brain, we examined the neuroinflammatory changes initiated by LPS administration to the cerebral ventricles of wild-type (WT) and Plexin-A1-deficient (-/-) mice. WT mice administered LPS exhibited a significantly higher expression of COX-2, iNOS, IL-1β and TNF-α in the hippocampus, and a significantly greater ventricular enlargement and intracerebral infiltration of leukocytes, as compared with the saline-treated group. By contrast, Plexin-A1-/- mice administered LPS did not exhibit a significantly increased expression of COX-2, iNOS, IL-1β or TNF-α in the hippocampus as compared with the saline‑treated group. Plexin-A1-/- mice administered LPS did not show significant increases in ventricle size or infiltration of leukocytes into the brain, as compared with the saline-treated group. In WT, but not in the Plexin-A1-/- primary microglia treated with LPS, Sema3A induced significantly more nitric oxide production than in the immunoglobulin G control. These results revealed the crucial role of the Sema3A-Plexin-A1 interaction in the Toll-like receptor 4-mediated signaling of the LPS-induced activation of microglia. Thus, results of the present study revealed the essential role of Plexin-A1 in the development of LPS-induced neuroinflammation in mice, suggesting the possible application of microglial control of the semaphorin-plexin signaling system to the treatment of LPS-induced encephalopathy and other psychiatric diseases associated with neuroinflammation.

View Figures

View References

1	Ransohoff RM and Perry VH: Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 27:119–145. 2009. View Article : Google Scholar : PubMed/NCBI
2	Heppner FL, Greter M, Marino D, et al: Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med. 11:146–152. 2005. View Article : Google Scholar : PubMed/NCBI
3	Jack C, Ruffini F, Bar-Or A and Antel JP: Microglia and multiple sclerosis. J Neurosci Res. 81:363–373. 2005. View Article : Google Scholar : PubMed/NCBI
4	Ponomarev ED, Shriver LP and Dittel BN: CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J Immunol. 176:1402–1410. 2006. View Article : Google Scholar
5	Lehnardt S, Lachance C, Patrizi S, et al: The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci. 22:2478–2486. 2002.PubMed/NCBI
6	Lehnardt S, Massillon L, Follett P, et al: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 100:8514–8519. 2003. View Article : Google Scholar : PubMed/NCBI
7	Heppner FL, Greter M, Marino D, et al: Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med. 11:146–152. 2005. View Article : Google Scholar : PubMed/NCBI
8	Tessier-Lavigne M and Goodman SC: The molecular biology of axon guidance. Science. 274:1123–1133. 1996. View Article : Google Scholar : PubMed/NCBI
9	Pasterkamp RJ and Kolodkin AL: Semaphorin junction: making tracks toward neural connectivity. Curr Opin Neurobiol. 13:79–89. 2003. View Article : Google Scholar : PubMed/NCBI
10	Sekido Y, Bader S, Latif F, et al: Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci USA. 93:4120–4125. 1996. View Article : Google Scholar : PubMed/NCBI
11	Gu C, Rodriguez ER, Reimert DV, et al: Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell. 5:45–57. 2003. View Article : Google Scholar : PubMed/NCBI
12	Toyofuku T, Zhang H, Kumanogoh A, et al: Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol. 6:1204–1211. 2004. View Article : Google Scholar : PubMed/NCBI
13	Kumanogoh A, Watanabe C, Lee I, et al: Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity. 13:621–631. 2000. View Article : Google Scholar : PubMed/NCBI
14	Shi W, Kumanogoh A, Watanabe C, et al: The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity. 13:633–642. 2000. View Article : Google Scholar : PubMed/NCBI
15	Kumanogoh A, Marukawa S, Suzuki K, et al: Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature. 419:629–633. 2002. View Article : Google Scholar : PubMed/NCBI
16	Kumanogoh A, Shikina T, Suzuki K, et al: Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity. 22:305–316. 2005. View Article : Google Scholar : PubMed/NCBI
17	Kikutani H and Kumanogoh A: Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol. 3:159–167. 2003. View Article : Google Scholar : PubMed/NCBI
18	Elhabazi A, Marie-Cardine A, Chabbert-de Ponnat I, Bensussan A and Boumsell L: Structure and function of the immune semaphorin CD100/SEMA4D. Crit Rev Immunol. 23:65–81. 2003. View Article : Google Scholar : PubMed/NCBI
19	Tamagnone L and Comoglio PM: Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol. 10:377–383. 2000. View Article : Google Scholar : PubMed/NCBI
20	Granziero L, Circosta P, Scielzo C, et al: CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood. 101:1962–1969. 2003.PubMed/NCBI
21	Walzer T, Galibert L, Comeau MR and De Smedt T: Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration. J Immunol. 174:51–59. 2005. View Article : Google Scholar
22	Takahashi T, Fournier A, Nakamura F, et al: Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell. 99:59–69. 1999. View Article : Google Scholar : PubMed/NCBI
23	Toyofuku T, Zhang H, Kumanogoh A, et al: Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev. 18:435–447. 2004. View Article : Google Scholar
24	Wong AW, Brickey WJ, Taxman DJ, et al: CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol. 4:891–898. 2003. View Article : Google Scholar : PubMed/NCBI
25	Shirvan A, Ziv I, Fleminger G, et al: Semaphorins as mediators of neuronal apoptosis. J Neurochem. 73:961–971. 1999. View Article : Google Scholar : PubMed/NCBI
26	Fujita H, Zhang B, Sato K, Tanaka J and Sakanaka M: Expressions of neuropilin-1, neuropilin-2 and semaphorin 3A mRNA in the rat brain after middle cerebral artery occlusion. Brain Res. 914:1–14. 2001. View Article : Google Scholar : PubMed/NCBI
27	Pasterkamp RJ and Verhaagen J: Emerging roles for semaphorins in neural regeneration. Brain Res Brain Res Rev. 35:36–54. 2001. View Article : Google Scholar : PubMed/NCBI
28	Majed HH, Chandran S, Niclou SP, et al: A novel role for Sema3A in neuroprotection from injury mediated by activated microglia. J Neurosci. 26:1730–1738. 2006. View Article : Google Scholar : PubMed/NCBI
29	Takegahara N, Takamatsu H, Toyofuku T, et al: Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol. 8:615–622. 2006. View Article : Google Scholar : PubMed/NCBI
30	Zhou H, Lapointe BM, Clark SR, Zbytnuik L and Kubes P: A requirement for microglial TLR4 in leukocyte recruitment into brain in response to lipopolysaccharide. J Immunol. 177:8103–8110. 2006. View Article : Google Scholar : PubMed/NCBI
31	Buttni M, Limonta S and Boddeke HW: Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain. Neurochem Int. 29:25–35. 1996.PubMed/NCBI
32	Grin’kina NM, Karnabi EE, Damania D, Wadgaonkar S, Muslimov IA and Wadgaonkar R: Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation. PLoS One. 7:e364752012.PubMed/NCBI
33	Banks WA and Erickson MA: The blood-brain barrier and immune function and dysfunction. Neurobiol Dis. 37:26–32. 2010. View Article : Google Scholar : PubMed/NCBI
34	Shaftel SS, Griffin WS and O’Banion MK: The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 5:72008. View Article : Google Scholar : PubMed/NCBI
35	Wen H, Lei Y, Eun SY and Ting JP: Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J Exp Med. 207:2943–2957. 2010. View Article : Google Scholar : PubMed/NCBI
36	Durrenberger PF, Facer P, Gray RA, et al: Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury. J Peripher Nerv Syst. 9:15–25. 2004. View Article : Google Scholar : PubMed/NCBI
37	Lehnardt S: Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 58:253–263. 2010.PubMed/NCBI
38	Shin WH, Lee DY, Park KW, et al: Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia. 46:142–152. 2004. View Article : Google Scholar : PubMed/NCBI
39	Lee J, Hur J, Lee P, et al: Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11. J Biol Chem. 276:32956–32965. 2001. View Article : Google Scholar
40	Yang MS, Ji KA, Jeon SB, et al: Interleukin-13 enhances cyclooxygenase-2 expression in activated rat brain microglia: implications for death of activated microglia. J Immunol. 177:1323–1329. 2006. View Article : Google Scholar : PubMed/NCBI
41	Choi SH, Aid S, Choi U and Bosetti F: Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenomics J. 10:448–457. 2010. View Article : Google Scholar : PubMed/NCBI
42	Burguillos MA, Deierborg T, Kavanagh E, et al: Caspase signalling controls microglia activation and neurotoxicity. Nature. 472:319–324. 2011. View Article : Google Scholar : PubMed/NCBI
43	Okuno T, Nakatsuji Y, Moriya M, et al: Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 184:1499–1506. 2010. View Article : Google Scholar : PubMed/NCBI