Microglial Cx3cr1 knockout reduces prion disease incubation time in mice

BMC Neuroscience

Sarah E Lloyd¹  John Collinge¹  Sebastian Brandner¹  Shaheen Akhtar¹  Julia Grizenkova¹ 

[1] MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

关键词: Chemokines;    Cytokines;    Microglia;    Cx3cr1;    Incubation time;    Prion disease;   

Others  :  799419
DOI  :  10.1186/1471-2202-15-44

 received in 2013-11-07, accepted in 2014-03-18,  发布年份 2014

【 摘 要 】

Background

Microglia are resident mononuclear phagocytes of the brain that become activated in response to insults including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and prion disease. In the central nervous system the chemokine Cx3cl1 (Fractalkine) is expressed by neurons and its exclusive receptor Cx3cr1 is expressed solely on microglia. Cx3cl1/Cx3cr1 signalling is thought to maintain microglia in their resting state and disrupting this equilibrium may allow microglia to become activated. In prion disease, microglial proliferation has been suggested to contribute to overall disease progression, however, in different mouse models of neurodegeneration, loss of Cx3cr1 has been shown to either worsen or improve the phenotype depending on the paradigm.

Results

To investigate the role of Cx3cl1/Cx3cr1 signalling in prion disease we infected Cx3cr1 null mice with three different strains of prions. Following challenge with Chandler/RML, ME7 and MRC2 prion strains, Cx3cr1 knockout mice showed highly significant reductions in incubation time. No differences were seen in the pattern and localisation of activated microglia in the brain or in the mRNA expression levels of chemokines/cytokines (Cxcl10, Il-12b, Il-1b, Arg-1 and Cxc3l1).

Conclusion

Our data suggest a protective role for Cx3cl1/Cx3cr1 cross-talk in prion disease.

【 授权许可】

   
2014 Grizenkova et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K: Development of monocytes, macrophages, and dendritic cells. Science 2010, 327:656-661.
• [2]Wolf Y, Yona S, Kim KW, Jung S: Microglia, seen from the CX(3)CR1 angle. Front Cell Neurosci 2013, 7:26.
• [3]Hanisch UK, Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387-1394.
• [4]Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH: Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 2002, 37:314-327.
• [5]Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR: Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 2000, 20:4106-4114.
• [6]Kim KW, Vallon-Eberhard A, Zigmond E, Farache J, Shezen E, Shakhar G, Ludwig A, Lira SA, Jung S: In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 2011, 118:E156-E167.
• [7]Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J: Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 2010, 13:411-413.
• [8]Lee S, Varvel NH, Konerth ME, Xu GX, Cardona AE, Ransohoff RM, Lamb BT: CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 2010, 177:2549-2562.
• [9]Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang DR, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006, 9:917-924.
• [10]Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J Neuroinflammation 2011, 8:9. BioMed Central Full Text
• [11]Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT: Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010, 68:19-31.
• [12]Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ: Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab 2008, 28:1707-1721.
• [13]Collinge J: Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 2001, 24:519-550.
• [14]Betmouni S, Perry VH, Gordon JL: Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience 1996, 74:1-5.
• [15]Perry VH, Cunningham C, Boche D: Atypical inflammation in the central nervous system in prion disease. Curr Opin Neurol 2002, 15:349-354.
• [16]Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH: Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 2013, 33:2481-2493.
• [17]Tribouillard-Tanvier D, Striebel JF, Peterson KE, Chesebro B: Analysis of protein levels of 24 cytokines in scrapie-infected brain and glial cell cultures of mice differing in prion protein expression. J Virol 2009, 83:11244-11253.
• [18]Xie WL, Shi Q, Zhang J, Zhang BY, Gong HS, Guo Y, Wang SB, Xu Y, Wang K, Chen C, Liu Y, Dong XP: Abnormal activation of microglia accompanied with disrupted CX3CR1/CX3CL1 pathway in the brains of the hamsters infected with scrapie agent 263K. J Mol Neurosci 2013, 51:919-932.
• [19]Grizenkova J, Akhtar S, Hummerich H, Tomlinson A, Asante EA, Wenborn A, Fizet J, Poulter M, Wiseman FK, Fisher EM, Tybulewicz VL, Brandner S, Collinge J, Lloyd SE: Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice. Proc Natl Acad Sci U S A 2012, 109:13722-13727.
• [20]Lloyd S, Linehan J, Desbruslais M, Joiner S, Buckell J, Brandner S, Wadsworth JD, Collinge J: Characterization of two distinct prion strains derived from bovine spongiform encephalopathy transmissions to inbred mice. J Gen Virol 2004, 85:2471-2478.
• [21]Lloyd S, Onwuazor ON, Beck J, Mallinson G, Farrall M, Targonski P, Collinge J, Fisher E: Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc Natl Acad Sci U S A 2001, 98:6279-6283.
• [22]O’Shea M, Maytham EG, Linehan JM, Brandner S, Collinge J, Lloyd S: Investigation of Mcp1 as a quantitative trait gene for prion disease incubation time in mouse. Genetics 2008, 180:559-566.
• [23]Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010, 8:e1000412.
• [24]Martinez FO: Regulators of macrophage activation. Eur J Immunol 2011, 41:1531-1534.