Abstract
Angiostrongylus cantonensis is an emerging zoonotic pathogen that has caused hundreds of cases of human angiostrongyliasis worldwide. The larva in nonpermissive hosts cannot develop into an adult worm and can cause eosinophilic meningitis and ocular angiostrongyliasis. The mechanism of brain inflammation caused by the worm remains poorly defined. According to previous data of GeneChip, Ym1 in the brain of mice 21 days after infection with A. cantonensis was highly upregulated to over 7,300 times than the untreated mice. Ym1 is an eosinophilic chemotactic factor with the alternative names of chitinase-3-like protein 3, eosinophil chemotactic cytokine, and ECF-L. Ym1 displays chemotactic activity for T lymphocytes, bone marrow cells, and eosinophils and may favor inflammatory responses induced by parasitic infections and allergy. It has been reported that Ym1 is synthesized and secreted by activated macrophages during parasitic infection (Chang et al., J Biol Chem 276(20):17497–17506, 2001). In the brain, microglia are alternatively activated macrophage-derived cells which are the key immune cells in central nervous system inflammation. To explore the role of Ym1 in inflammation caused by A. cantonensis-infected mice, we examined the levels of Ym1 in the sera and cerebrospinal fluid (CSF) of the infected animals, followed by detection of the mRNA expression level of Ym1 in various organs including the brain, lung, liver, spleen, and kidney and of the cytokines IL-5 and IL-13 in the brain of the infected mice with or without intraperitoneal injection of minocycline (an inhibitor of microglial activation) by real-time reserve transcription PCR. Furthermore, immunolocalization of Ym1 in the brains of the infected mice was observed by using a fluorescence microscope. Our results showed that Ym1 was most highly expressed in the brains and CSF of the infected mice along with the process of inflammation. The antibody localized Ym1 to the microglia in the brain of the mice in both infection and minocycline + infection groups. And as in the brain, the mRNA level of Ym1 changed more obviously than IL-5 and IL-13. The study implies that Ym1 might serve as an alternative potential pathological marker which is detected not only in the sera and CSF but also in the brains of the infected mice and Ym1 secreted by microglia might be involved in eosinophilic meningitis and meningoencephalitis caused by A. cantonensis infection.
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References
Cai Y, Kumar RK, Zhou J, Foster PS, Webb DC (2009) Ym1/2 promotes Th2 cytokine expression by inhibiting 12/15(S)-lipoxygenase: identification of a novel pathway for regulating allergic inflammation. J Immunol 182(9):5393–5399
Chang NC, Hung SI, Hwa KY, Kato I, Chen JE, Liu CH, Chang AC (2001) A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem 276(20):17497–17506
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27
Creuzet C, Robert F, Roisin MP, Van Tan H, Benes C, Dupouy-Camet J, Fagard R (1998) Neurons in primary culture are less efficiently infected by Toxoplasma gondii than glial cells. Parasitol Res 984(1):25–30
Dellacasa-Lindberg I, Fuks JM, Arrighi RB, Lambert H, Wallin RP, Chambers BJ, Barragan A (2011) Migratory activation of primary cortical microglia upon infection with Toxoplasma gondii. Infect Immun 79(8):3046–3052
Dissing-Olesen L, Ladeby R, Nielsen HH, Toft-Hansen H, Dalmau I, Finsen B (2007) Axonal lesion-induced microglial proliferation and microglial cluster formation in the mouse. Neuroscience 149(1):112–122
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20(3):269–287
Fischer HG, Nitzgen B, Reichmann G, Gross U, Hadding U (1997) Host cells of Toxoplasma gondii encystation in infected primary culture from mouse brain. Parasitol Res 83(7):637–641
Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H, Suzumura A, Ishiguro N (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525
Kouro T, Takatsu K (2009) IL-5- and eosinophil-mediated inflammation from discovery to therapy. Int Immunol 21(12):1303–1309
Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48(2):405–415
Lee HH, Chou HL, Chen KM, Lai SC (2004) Association of matrix metalloproteinase-9 in eosinophilic meningitis of BALB/c mice caused by Angiostrongylus cantonensis. Parasitol Res 94(5):321–328
Mishra A, Rothenberg ME (2003) Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 125(5):1419–1427
Misson P, van den Brule S, Barbarin V, Lison D, Huaux F (2004) Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol 76(5):926–932
Mylonas KJ, Nair MG, Prieto-Lafuente L, Paape D, Allen JE (2009) Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing. J Immunol 182(5):3084–3094
Nair MG, Gallagher IJ, Taylor MD, Loke P, Coulson PS, Wilson RA, Maizels RM, Allen JE (2005) Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 73(1):385–394
Owhashi M, Arita H, Hayai N (2000) Identification of a novel eosinophil chemotactic cytokine (ECF-L) as a chitinase family protein. J Biol Chem 275(2):1279–1286
Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8:174
Pope SM, Brandt EB, Mishra A, Hogan SP, Zimmermann N, Matthaei KI, Foster PS, Rothenberg ME (2001) IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J Allergy Clin Immunol 108(4):594–601
Rosenberg HF, Dyer KD, Foster PS (2013) Eosinophils: changing perspectives in health and disease. Nat Rev Immunol 13(1):9–22
Sawanyawisuth K, Takahashi K, Hoshuyama T, Sawanyawisuth K, Senthong V, Limpawattana P, Intapan PM, Wilson D, Tiamkao S, Jitpimolmard S (2009) Clinical factors predictive of encephalitis caused by Angiostrongylus cantonensis. AmJTrop Med Hyg 81(4):698–701
Sehmi R, Wardlaw AJ, Cromwell O, Kurihara K, Waltmann P, Kay AB (1992) Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. Blood 79(11):2952–2959
Tsai HC, Tseng YT, Yen CM, Chen ER, Sy CL, Lee SS, Wann SR, Chen YS (2012) Brain magnetic resonance imaging abnormalities in eosinophilic meningitis caused by Angiostrongylus cantonensis infection. Vector Borne Zoonotic Dis 12(2):161–166
Wei J, Wu F, Sun X, Zeng X, Liang JY, Zheng HQ, Yu XB, Zhang KX, Wu ZD (2013) Differences in microglia activation between rats-derived cell and mice-derived cell after stimulating by soluble antigen of IV larva from Angiostrongylus cantonensis in vitro. Parasitol Res 112(1):207–214
Welch JS, Escoubet-Lozach L, Sykes DB, Liddiard K, Greaves DR, Glass CK (2002) Th2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J Biol Chem 277(45):42821–42829
Yang X, Qu Z, He H, Zheng X, He A, Wu Y, Liu Q, Zhang D, Wu Z, Li Z, Zhan X (2012) Enzootic angiostrongyliasis in Guangzhou, China, 2008–2010. AmJTrop Med Hyg 86(5):846–849
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This work was supported by the National Basic Research Program of China (973 Program) (grant no. 2010CB53004), the National Natural Science Foundation of China (grant nos. 81261160324 and 8127855), and the National S&T Major Program (grant nos. 2012ZX10004-220 and 2008ZX10004-011).
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Jia Zhao and Zhiyue Lv have equal contribution to the study.
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Zhao, J., Lv, Z., Wang, F. et al. Ym1, an eosinophilic chemotactic factor, participates in the brain inflammation induced by Angiostrongylus cantonensis in mice. Parasitol Res 112, 2689–2695 (2013). https://doi.org/10.1007/s00436-013-3436-x
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DOI: https://doi.org/10.1007/s00436-013-3436-x