Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Activation of Autophagy Pathway Suppresses the Expression of iNOS, IL6 and Cell Death of LPS-Stimulated Microglia Cells

  • Han, Hye-Eun (Department of Life Science, Gwangju Institute of Science and Technology (GIST)) ;
  • Kim, Tae-Kyung (Department of Brain and Cognitive Sciences, Ewha Womans University) ;
  • Son, Hyung-Jin (Department of Brain and Cognitive Sciences, Ewha Womans University) ;
  • Park, Woo Jin (Department of Life Science, Gwangju Institute of Science and Technology (GIST)) ;
  • Han, Pyung-Lim (Department of Brain and Cognitive Sciences, Ewha Womans University)
  • Received : 2012.11.13
  • Accepted : 2013.01.03
  • Published : 2013.01.31
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Abstract

Microglia play a role in maintaining and resolving brain tissue homeostasis. In pathological conditions, microglia release pro-inflammatory cytokines and cytotoxic factors, which aggravate the progression of neurodegenerative diseases. Autophagy pathway might be involved in the production of pro-inflammatory cytokines and cytotoxic factors in microglia, though details of the mechanism remain largely unknown. In the present study, we examined the role of the autophagy pathway in activated BV2 microglia cells. In BV2 cells, rapamycin treatment activated the formation of anti-LC3-labeled autophagosomes, whereas the ATG5 depletion using siRNA-ATG5 prevented the formation of LC3-labeled autophagosomes, indicating that BV2 cells exhibit an active classical autophagy system. When treated with LPS, BV2 cells expressed an increase of anti-LC3-labeled dots. The levels of LC3-labeled dots were not suppressed, instead tended to be enhanced, by the inhibition of the autophagy pathway with siRNA-ATG5 or wortmannin, suggesting that LPS-induced LC3-labeled dots in nature were distinct from the typical autophagosomes. The levels of LPS-induced expression of iNOS and IL6 were suppressed by treatment with rapamycin, and conversely, their expressions were enhanced by siRNA-ATG5 treatment. Moreover, the activation of the autophagy pathway using rapamycin inhibited cell death of LPS-stimulated microglia. These results suggest that although microglia possess a typical autophagy pathway, the glial cells express a non-typical autophagy pathway in response to LPS, and the activation of the autophagy pathway suppresses the expression of iNOS and IL6, and the cell death of LPS-stimulated microglia.

Keywords

References

  1. Akar, U., Chaves-Reyez, A., Barria, M., Tari, A., Sanguino, A., Kondo, Y., Kondo, S., Arun, B., Lopez-Berestein, G. and Ozpolat, B. (2008) Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 4, 669-679. https://doi.org/10.4161/auto.6083
  2. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., Finch, C. E., Frautschy, S., Griffin W. S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I. R., McGeer, P. L., O'Banion, M. K., Pachter J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F. L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G. and Wyss-Coray, T. (2000) Inflammation and Alzheimer's disease. Neurobiol. Aging 2, 383-421.
  3. Alirezaei, M., Kiosses, W. B. and Fox, H. S. (2008) Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 4, 963-966. https://doi.org/10.4161/auto.6805
  4. Beurel, E. and Jope, R. S. (2009) Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J. Neuroinflammation 6, 9. https://doi.org/10.1186/1742-2094-6-9
  5. Canadien, V., Tan, T., Zilber, R., Szeto, J., Perrin, A. J. and Brumell, J. H. (2005) Cutting edge: microbial products elicit formation of dendritic cell aggresome-like induced structures in macrophages. J. Immunol. 174, 2471-2475. https://doi.org/10.4049/jimmunol.174.5.2471
  6. Eriksson, U. K., Pedersen, N. L., Reynolds, C. A., Hong, M. G., Prince, J. A., Gatz, M., Dickman, P. W. and Bennet, A. M. (2011) Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer's disease and dementia. J. Alzheimers Dis. 23, 361-369.
  7. Fujita, K., Maeda, D., Xiao, Q. and Srinivasula, S. M. (2011) Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation. Proc. Natl. Acad. Sci. USA 108, 1427-1432. https://doi.org/10.1073/pnas.1014156108
  8. Gehrmann, J., Matsumoto, Y. and Kreutzberg, G. W. (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res. Rev. 20, 269-287. https://doi.org/10.1016/0165-0173(94)00015-H
  9. Gross, S. S. and Wolin, M. S. (1995) Nitric oxide: pathophysiological mechanisms. Annu. Rev. Physiol. 57, 737-769. https://doi.org/10.1146/annurev.ph.57.030195.003513
  10. Han, H. E., Sellamuthu S, Shin, B.H., Lee, Y.J., Song, S., Seo, J. S., Beak, I. S., Bae, J., Kim, H., Yoo, Y. J., Jung, Y. K., Song, W. K., Han, P. L. and Park, W. J. (2010) The nuclear inclusion a (NIa) protease of turnip mosaic virus (TuMV) cleaves amyloid-$\beta$. PLoS One 5, e15645. https://doi.org/10.1371/journal.pone.0015645
  11. Hanisch, U. K. (2002) Microglia as a source and target of cytokines. Glia 40, 140-155. https://doi.org/10.1002/glia.10161
  12. Henkel, J. S., Beers, D. R., Zhao, W. and Appel, S. H. (2009) Microglia in ALS: the good, the bad, and the resting. J. Neuroimmune Pharmacol. 4, 389-398. https://doi.org/10.1007/s11481-009-9171-5
  13. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. and Ross, M. E. (1997) Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17, 9157-9164.
  14. Im, J. Y., Joo, H. J. and Han, P. L. (2011) Rapid disruption of cellular integrity of Zinc-treated astroglia is regulated by p38MAPK and $Ca^{2+}$-dependent mechanisms. Exp. Neurobiol. 20, 45-53. https://doi.org/10.5607/en.2011.20.1.45
  15. Kabeya, Y., Mizushima N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y. and Yoshimori, T. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728. https://doi.org/10.1093/emboj/19.21.5720
  16. Kim, S. W. and Lee, J. K. (2007) NO-induced downregulation of HSP10 and HSP60 expression in the postischemic brain. J. Neurosci. Res. 85, 1252-1259. https://doi.org/10.1002/jnr.21236
  17. Lee, J., Kim, H. R., Quinley, C., Kim, J., Gonzalez-Navajas, J., Xavier, R. and Raz, E. (2012) Autophagy suppresses interleukin-1$\beta$ (IL-1$\beta$) signaling by activation of p62 degradation via lysosomal and proteasomal pathways. J. Biol. Chem. 287, 4033-4040. https://doi.org/10.1074/jbc.M111.280065
  18. Lee, J. H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., Wolfe, D. M., Martinez-Vicente, M., Massey, A. C., Sovak, G., Uchiyama, Y., Westaway, D., Cuervo, A. M. and Nixon, R. A. (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146-1158. https://doi.org/10.1016/j.cell.2010.05.008
  19. Lelouard, H., Ferrand, V., Marguet, D., Bania, J., Camosseto, V., David, A., Gatti, E. and Pierre, P. (2004) Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins. J. Cell Biol. 164, 667-675. https://doi.org/10.1083/jcb.200312073
  20. Lelouard, H., Gatti E., Cappello, F., Gresser, O., Camosseto, V. and Pierre P. (2002) Transient aggregation of ubiquitinated proteins during dendritic cell maturation. Nature 417, 177-182. https://doi.org/10.1038/417177a
  21. Levine, B. and Klionsky, D. J. (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463-477. https://doi.org/10.1016/S1534-5807(04)00099-1
  22. Lu, Y. C., Yeh, W. C. and Ohashi, P. S. (2008) LPS/TLR4 signal transduction pathway. Cytokine 42, 145-151. https://doi.org/10.1016/j.cyto.2008.01.006
  23. Magazine, H. I., Liu, Y., Bilfinger, T. V., Fricchione, G. L. and Stefano, G. B. (1996) Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide. J. Immunol. 156, 4845-4850.
  24. Matsumoto, Y., Ohmori, K. and Fujiwara, M. (1992) Microglial and astroglial reactions to inflammatory lesions of experimental autoimmune encephalomyelitis in the rat central nervous system. J. Neuroimmunol. 37, 23-33. https://doi.org/10.1016/0165-5728(92)90152-B
  25. Mayo, L. and Stein, R. (2007) Characterization of LPS and interferon-gamma triggered activation-induced cell death in N9 and primary microglial cells: induction of the mitochondrial gateway by nitric oxide. Cell Death Differ. 14, 183-186. https://doi.org/10.1038/sj.cdd.4401989
  26. McGeer, P. L., Itagaki, S., Boyes, B. E. and McGeer, E. G. (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285-1291. https://doi.org/10.1212/WNL.38.8.1285
  27. Nakagawa, I., Amano, A., Mizushima, N., Yamamoto, A., Yamaguchi, H., Kamimoto, T., Nara, A., Funao, J., Nakata, M., Tsuda, K., Hamada, S. and Yoshimori, T. (2004) Autophagy defends cells against invading group A Streptococcus. Science 306, 1037-1040. https://doi.org/10.1126/science.1103966
  28. Nakahira, K., Haspel, J. A., Rathinam, V. A., Lee, S. J., Dolinay, T., Lam, H. C., Englert, J. A., Rabinovitch, M., Cernadas, M., Kim, H. P., Fitzgerald, K. A., Ryter, S. W. and Choi, A. M. (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230.
  29. Nixon, R. A. and Yang, D. S. (2011) Autophagy failure in Alzheimer's disease--locating the primary defect. Neurobiol. Dis. 43, 38-45. https://doi.org/10.1016/j.nbd.2011.01.021
  30. Perry, V. H., Nicoll, J. A. and Holmes, C. (2010) Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193-201. https://doi.org/10.1038/nrneurol.2010.17
  31. Raine, C. S. (1994) Multiple sclerosis: immune system molecule expression in the central nervous system. J. Neuropathol. Exp. Neurol. 53, 328-337. https://doi.org/10.1097/00005072-199407000-00002
  32. Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J. and Rubinsztein, D. C. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585-595. https://doi.org/10.1038/ng1362
  33. Rosello, A., Warnes, G. and Meier, U. C. (2012) Cell death pathways and autophagy in the central nervous system and its involvement in neurodegeneration, immunity and central nervous system infection: to die or not to die--that is the question. Clin. Exp. Immunol. 168, 52-57. https://doi.org/10.1111/j.1365-2249.2011.04544.x
  34. Saitoh, T., Fujita, N., Jang, M. H., Uematsu, S., Yang, B. G., Satoh, T., Omori, H., Noda, T., Yamamoto, N., Komatsu, M., Tanaka, K., Kawai, T., Tsujimura, T., Takeuchi, O., Yoshimori, T. and Akira, S. (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264-268. https://doi.org/10.1038/nature07383
  35. Sarkar, S. and Rubinsztein, D. C. (2008) Small molecule enhancers of autophagy for neurodegenerative diseases. Mol. Biosyst. 4, 895-901. https://doi.org/10.1039/b804606a
  36. Semmler, A., Frisch, C., Debeir, T., Ramanathan, M., Okulla, T., Klockgether, T. and Heneka, M. T. (2007) Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp. Neurol. 204, 733-740. https://doi.org/10.1016/j.expneurol.2007.01.003
  37. Shi, C. S. and Kehrl, J. H. (2008) MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J. Biol. Chem. 283, 33175-33182. https://doi.org/10.1074/jbc.M804478200
  38. Sims, K., Haynes, C. A., Kelly, S., Allegood, J. C., Wang, E., Momin, A., Leipelt, M., Reichart, D., Glass, C. K., Sullards, M. C. and Merrill, A. H. Jr. (2010) Kdo2-lipid A, a TLR4-specific agonist, induces de novo sphingolipid biosynthesis in RAW264.7 macrophages, which is essential for induction of autophagy. J. Biol. Chem. 285, 38568-38579. https://doi.org/10.1074/jbc.M110.170621
  39. Singh, S. B., Davis, A. S., Taylor, G. A. and Deretic, V. (2006) Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438-1441. https://doi.org/10.1126/science.1129577
  40. Smith, J. A., Das, A., Ray, S. K. and Banik, N. L. (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 87, 10-20. https://doi.org/10.1016/j.brainresbull.2011.10.004
  41. Strauss, S., Bauer, J., Ganter, U., Jonas, U., Berger, M. and Volk, B. (1992) Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. Lab. Invest. 66, 223-230.
  42. Szeto, J., Kaniuk, N. A., Canadien, V., Nisman, R., Mizushima, N., Yoshimori, T., Bazett-Jones, D. P. and Brumell, J. H. (2006) ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy. Autophagy 2, 189-199. https://doi.org/10.4161/auto.2731
  43. Virgin, H. W. and Levine, B. (2009) Autophagy genes in immunity. Nat. Immunol. 10, 461-470. https://doi.org/10.1038/ni.1726
  44. Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D. K., Ischiropoulos, H. and Przedborski, S. (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763-1771.
  45. Xu, Y., Jagannath, C., Liu, X. D., Sharafkhaneh, A., Kolodziejska, K. E. and Eissa, N. T. (2007) Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135-144. https://doi.org/10.1016/j.immuni.2007.05.022
  46. Yu, Y. M., Kim, J. B., Lee, K. W., Kim, S. Y., Han, P. L. and Lee, J. K. (2005) Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window. Stroke 36, 2238-2243. https://doi.org/10.1161/01.STR.0000181779.83472.35
  47. Yuan, K., Huang, C., Fox, J., Laturnus, D., Carlson, E., Zhang, B., Yin, Q., Gao, H. and Wu, M. (2012) Autophagy plays an essential role in the clearance of Pseudomonas aeruginosa by alveolar macrophages. J. Cell Sci. 125, 507-515. https://doi.org/10.1242/jcs.094573
  48. Zhang, F., Casey, R. M., Ross, M. E. and Iadecola, C. (1996) Aminoguanidine ameliorates and L-arginine worsens brain damage from intraluminal middle cerebral artery occlusion. Stroke 27, 317-323. https://doi.org/10.1161/01.STR.27.2.317
  49. Zoncu, R., Efeyan, A. and Sabatini, D. M. (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21-35. https://doi.org/10.1038/nrm3025

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