Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

Journal of Neuroinflammation

John Hallenbeck¹  Modinat Lawal¹  Maria Spatz¹  YongshanMou¹  Bolanle Famakin¹ 

[1] Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 5B06, MSC 1401, Bethesda, MD 20892-1401, USA

关键词: Leukocytes;    Neutrophils;    Receptor;    Toll-like;    TLR signaling;    Cytokines;    MCAO;    Focal ischemia;    TRIF;    MyD88;   

Others  :  1160370
DOI  :  10.1186/1742-2094-9-174

 received in 2011-12-05, accepted in 2012-06-14,  发布年份 2012

【 摘 要 】

Background

Deletion of some Toll-like receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT), MyD88^−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO).

Methods

Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO.

Results

IL-6, keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (G-CSF) and IL-10 were significantly decreased in MyD88^−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88^−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. Finally, MyD88^−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO.

Conclusions

Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88^−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. Finally, the MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

【 授权许可】

   
2012 Famakin et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1 .

Figure 2 .

Figure 3 .

Figure 4 .

Figure 5 .

【 参考文献 】

• [1]Takeda K, Akira S: TLR signaling pathways. Semin Immunol 2004, 16:3-9.
• [2]Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM: Toll-like receptors in ischemia-reperfusion injury. Shock 2009, 32:4-16.
• [3]Wang YC, Lin S, Yang QW: Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation 2011, 8:134.
• [4]Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305.
• [5]Medzhitov R: Toll-like receptors and innate immunity. Nat Rev 2001, 1:135-145. Immunology
• [6]Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I: Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007, 115:1599-1608.
• [7]Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, Konig J, Lehrach H, Nietfeld W, Trendelenburg G: TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 2007, 359:574-579.
• [8]Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP: Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 2007, 104:13798-13803.
• [9]Famakin BM, Mou Y, Ruetzler CA, Bembry J, Maric D, Hallenbeck JM: Disruption of downstream MyD88 or TRIF Toll-like receptor signaling does not protect against cerebral ischemia. Brain Res 2011, 1388:148-156.
• [10]Tsung A, Stang MT, Ikeda A, Critchlow ND, Izuishi K, Nakao A, Chan MH, Jeyabalan G, Yim JH, Geller DA: The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2006, 290:G1261-G1268.
• [11]Hua F, Ha T, Ma J, Gao X, Kelley J, Williams DL, Browder IW, Kao RL, Li C: Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts. Biochem Biophys Res Commun 2005, 338:1118-1125.
• [12]Shigeoka AA, Holscher TD, King AJ, Hall FW, Kiosses WB, Tobias PS, Mackman N, McKay DB: TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J Immunol 2007, 178:6252-6258.
• [13]Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C: Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 2002, 22:308-317.
• [14]Brown HC, Kristenssen T, Rothaul A, Perry VH: The influence of plasma proteins on the distribution of leucocytes within the brain parenchyma in a murine model of stroke. Neuropathol Appl Neurobiol 1998, 24:177-186.
• [15]Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S: Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998, 9:143-150.
• [16]Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B: Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003, 424:743-748.
• [17]Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T, Mihara M, Ohsugi Y, Abe K, Okano H: Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 2005, 94:459-468.
• [18]Clark WM, Rinker LG, Lessov NS, Hazel K, Eckenstein F: Time course of IL-6 expression in experimental CNS ischemia. Neurol Res 1999, 21:287-292.
• [19]Clark WM, Rinker LG, Lessov NS, Hazel K, Hill JK, Stenzel-Poore M, Eckenstein F: Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke 2000, 31:1715-1720.
• [20]Bozic CR, Kolakowski LF, Gerard NP, Garcia-Rodriguez C, von Uexkull-Guldenband C, Conklyn MJ, Breslow R, Showell HJ, Gerard C: Expression and biologic characterization of the murine chemokine KC. J Immunol 1995, 154:6048-6057.
• [21]De Filippo K, Henderson RB, Laschinger M, Hogg N: Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways. J Immunol 2008, 180:4308-4315.
• [22]Cai S, Batra S, Shen L, Wakamatsu N, Jeyaseelan S: Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. J Immunol 2009, 183:6629-6638.
• [23]Ventura GMD, Balloy V, Ramphal R, Khun H, Huerre M, Ryffel B, Plotkowski MCM, Chignard M, Si-Tahar M: Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia. J Immunol 2009, 183:670-676.
• [24]Hasselblatt M, Jeibmann A, Riesmeier B, Maintz D, Schabitz WR: Granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor expression in human ischemic stroke. Acta Neuropathol 2007, 113:45-51.
• [25]Popa-Wagner A, Stocker K, Balseanu AT, Rogalewski A, Diederich K, Minnerup J, Margaritescu C, Schabitz WR: Effects of granulocyte-colony stimulating factor after stroke in aged rats. Stroke 2010, 41:1027-1031.
• [26]Sevimli S, Diederich K, Strecker JK, Schilling M, Klocke R, Nikol S, Kirsch F, Schneider A, Schabitz WR: Endogenous brain protection by granulocyte-colony stimulating factor after ischemic stroke. Exp Neurol 2009, 217:328-335.
• [27]Solaroglu I, Cahill J, Tsubokawa T, Beskonakli E, Zhang JH: Granulocyte colony-stimulating factor protects the brain against experimental stroke via inhibition of apoptosis and inflammation. Neurol Res 2009, 31:167-172.
• [28]Solaroglu I, Tsubokawa T, Cahill J, Zhang JH: Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience 2006, 143:965-974.
• [29]Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Torres F, Planas AM: Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke. J Neurol Neurosurg Psychiatry 2006, 77:1279-1281.
• [30]Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD: Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006, 26:654-665.
• [31]Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R: Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2001, 2:947-950.
• [32]von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Aróstegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yagüe J, Antón J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Maródi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL: Pyogenic bacterial infections in humans with MyD88 deficiency. Science 2008, 321:691-696.
• [33]Nance SC, Yi AK, Re FC, Fitzpatrick EA: MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis. J Leukoc Biol 2008, 83:1207-1217.