Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury

Authors: Heidi Y. Febinger, Hannah E. Thomasy, Maria N. Pavlova, Kristyn M. Ringgold, Paulien R. Barf, Amrita M. George, Jenna N. Grillo, Adam D. Bachstetter, Jenny A. Garcia, Astrid E. Cardona, Mark R. Opp, Carmelina Gemma

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

Abstract

Background

Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases.

Methods

In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury.

Results

During the acute post-injury period (24 h–15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1−/− mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1−/− mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1−/− mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFβ. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI.

Conclusion

Collectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.
Literature
1.
Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70(3):374–83.PubMedCrossRef
2.
Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, Tan J. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention. J Neuroinflammation. 2012;9:185.PubMedCrossRefPubMedCentral
3.
Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Front Neurol. 2013;4:30.PubMedCrossRefPubMedCentral
4.
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000;20(11):4106–14.PubMedCrossRefPubMedCentral
5.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9(7):917–24.PubMedCrossRef
6.
Mizuno T, Kawanokuchi J, Numata K, Suzumura A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res. 2003;979(1–2):65–70.PubMedCrossRef
7.
Limatola C, Lauro C, Catalano M, Ciotti MT, Bertollini C, Di AS, et al. Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity. J Neuroimmunol. 2005;166(1–2):19–28.PubMedCrossRef
8.
Meucci O, Fatatis A, Simen AA, Miller RJ. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci U S A. 2000;97(14):8075–80.PubMedCrossRefPubMedCentral
9.
10.
Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease—a double-edged sword. Neuron. 2002;35(3):419–32.PubMedCrossRef
11.
12.
Yoshida H, Imaizumi T, Fujimoto K, Matsuo N, Kimura K, Cui X, et al. Synergistic stimulation, by tumor necrosis factor-alpha and interferon-gamma, of fractalkine expression in human astrocytes. Neurosci Lett. 2001;303(2):132–6.PubMedCrossRef
13.
Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J, Kawaguchi N, et al. Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? FEBS Lett. 1998;429(2):167–72.PubMedCrossRef
14.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A. 1998;95(18):10896–901.PubMedCrossRefPubMedCentral
15.
Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA, et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature. 1997;387(6633):611–7.PubMedCrossRef
16.
Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU. Fractalkine and fractalkine receptors in human neurons and glial cells. J Neurosci Res. 2002;69(3):418–26.PubMedCrossRef
17.
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(1):19–31.PubMedCrossRefPubMedCentral
18.
Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 Deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177(5):2549–62.PubMedCrossRefPubMedCentral
19.
Ransohoff RM, Liu L, Cardona AE. Chemokines and chemokine receptors: multipurpose players in neuroinflammation. Int Rev Neurobiol. 2007;82:187–204.PubMedCrossRef
20.
Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, et al. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem. 2011;286(37):32713–22.PubMedCrossRefPubMedCentral
21.
Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci. 2010;13(4):411–3.PubMedCrossRefPubMedCentral
22.
Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010;30(50):17091–101.PubMedCrossRefPubMedCentral
23.
Donnelly DJ, Longbrake EE, Shawler TM, Kigerl KA, Lai W, Tovar CA, et al. Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci. 2011;31(27):9910–22.PubMedCrossRefPubMedCentral
24.
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(10):1707–21.PubMedCrossRef
25.
Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E, et al. CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011;31(45):16327–35.PubMedCrossRef
26.
Fumagalli S, Perego C, Ortolano F, de Simoni MG. CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia. 2013;61(6):827–42.PubMedCrossRef
27.
Rancan M, Bye N, Otto VI, Trentz O, Kossmann T, Frentzel S, et al. The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury. J Cereb Blood Flow Metab. 2004;24(10):1110–8.PubMedCrossRef
28.
Gaetani P, Pisano P, Solinas G, Colombo P, Destro A, Levi D, et al. Immunohistohemical expression of the chemokine fractalkine and its receptor in the human brain cortex after severe traumatic brain injury and brain hemorrhage. J Neurosurg Sci. 2013;57(1):55–62.PubMed
29.
Chhor V, Le CT, Lebon S, Ore MV, Celador IL, Josserand J, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun. 2013;32:70–85.PubMedCrossRefPubMedCentral
30.
31.
32.
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation. 2006;3:27.PubMedCrossRefPubMedCentral
33.
34.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.PubMedCrossRef
35.
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29(43):13435–44.PubMedCrossRefPubMedCentral
36.
Washington PM, Forcelli PA, Wilkins T, Zapple DN, Parsadanian M, Burns MP. The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J Neurotrauma. 2012;29(13):2283–96.PubMedCrossRefPubMedCentral
37.
Bolkvadze T, Pitkanen A. Development of post-traumatic epilepsy after controlled cortical impact and lateral fluid-percussion-induced brain injury in the mouse. J Neurotrauma. 2012;29(5):789–812.PubMedCrossRef
38.
Kubova H, Druga R, Lukasiuk K, Suchomelova L, Haugvicova R, Jirmanova I, et al. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J Neurosci. 2001;21(10):3593–9.PubMed
39.
West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991;231(4):482–97.PubMedCrossRef
40.
Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011;31(45):16241–50.PubMedCrossRef
41.
Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol. 2012;188(1):29–36.PubMedCrossRefPubMedCentral
42.
43.
Garcia JA, Pino PA, Mizutani M, Cardona SM, Charo IF, Ransohoff RM, et al. Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. J Immunol. 2013;191(3):1063–72.PubMedCrossRefPubMedCentral
44.
45.
Neher JJ, Neniskyte U, Brown GC. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front Pharmacol. 2012;3:27.PubMedCrossRefPubMedCentral
46.
Zanier ER, Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S, et al. Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma. Neurotherapeutics. 2014;11(3):679–95.PubMedCrossRefPubMedCentral
47.
Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7(4):483–95.PubMedCrossRefPubMedCentral
48.
Sierra A, Abiega O, Shahraz A, Neumann H. Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci. 2013;7:6.PubMedCrossRefPubMedCentral
49.
Wang G, Zhang J, Hu X, Zhang L, Mao L, Jiang X, et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab. 2013;33(12):1864–74.PubMedCrossRefPubMedCentral
50.
Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, et al. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci. 2015;35(2):748–60.PubMedCrossRefPubMedCentral
51.
Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71–82.PubMedCrossRef
52.
Combadiere C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117(13):1649–57.PubMedCrossRef
53.
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.PubMedCrossRefPubMedCentral
54.
Thawer SG, Mawhinney L, Chadwick K, de Chickera SN, Weaver LC, Brown A, et al. Temporal changes in monocyte and macrophage subsets and microglial macrophages following spinal cord injury in the Lys-Egfp-ki mouse model. J Neuroimmunol. 2013;261(1–2):7–20.PubMedCrossRef
55.
Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007;204(5):1057–69.PubMedCrossRefPubMedCentral
56.
Lin SL, Castano AP, Nowlin BT, Lupher Jr ML, Duffield JS. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol. 2009;183(10):6733–43.PubMedCrossRef
57.
Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003;111(3):333–40.PubMedCrossRefPubMedCentral
58.
Tang Z, Gan Y, Liu Q, Yin JX, Liu Q, Shi J, et al. CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation. 2014;11:26.PubMedCrossRefPubMedCentral
Metadata
Title
Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury
Authors
Heidi Y. Febinger
Hannah E. Thomasy
Maria N. Pavlova
Kristyn M. Ringgold
Paulien R. Barf
Amrita M. George
Jenna N. Grillo
Adam D. Bachstetter
Jenny A. Garcia
Astrid E. Cardona
Mark R. Opp
Carmelina Gemma
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0386-5

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue

Research

Neuronal self-injury mediated by IL-1β and MMP-9 in a cerebral palsy model of severe neonatal encephalopathy induced by immune activation plus hypoxia-ischemia

Research

The spinal anti-inflammatory mechanism of motor cortex stimulation: cause of success and refractoriness in neuropathic pain?

Research

The disruption of mitochondrial axonal transport is an early event in neuroinflammation

Research

Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay

Research

Pentraxin 3 mediates neurogenesis and angiogenesis after cerebral ischaemia

Research

Immunoglobulins stimulate cultured Schwann cell maturation and promote their potential to induce axonal outgrowth