Role of CCL2 (MCP-1) in Traumatic Brain Injury (TBI): Evidence from Severe TBI Patients and CCL2-/- Mice

Overview

Journal J Cereb Blood Flow Metab

Publisher Sage Publications

Specialties Cardiology & Vascular Diseases
Endocrinology
Neurology

Date 2009 Dec 24

PMID 20029451

Citations 193

Authors

Bridgette D Semple

Nicole Bye

Mario Rancan

Jenna M Ziebell

M Cristina Morganti-Kossmann

Affiliations

Soon will be listed here.

Abstract

Cerebral inflammation involves molecular cascades contributing to progressive damage after traumatic brain injury (TBI). The chemokine CC ligand-2 (CCL2) (formerly monocyte chemoattractant protein-1, MCP-1) is implicated in macrophage recruitment into damaged parenchyma after TBI. This study analyzed the presence of CCL2 in human TBI, and further investigated the role of CCL2 in physiological and cellular mechanisms of secondary brain damage after TBI. Sustained elevation of CCL2 was detected in the cerebrospinal fluid (CSF) of severe TBI patients for 10 days after trauma, and in cortical homogenates of C57Bl/6 mice, peaking at 4 to 12 h after closed head injury (CHI). Neurological outcome, lesion volume, macrophage/microglia infiltration, astrogliosis, and the cerebral cytokine network were thus examined in CCL2-deficient (-/-) mice subjected to CHI. We found that CCL2-/- mice showed altered production of multiple cytokines acutely (2 to 24 h); however, this did not affect lesion size or cell death within the first week after CHI. In contrast, by 2 and 4 weeks, a delayed reduction in lesion volume, macrophage accumulation, and astrogliosis were observed in the injured cortex and ipsilateral thalamus of CCL2-/- mice, corresponding to improved functional recovery as compared with wild-type mice after CHI. Our findings confirm the significant role of CCL2 in mediating post-traumatic secondary brain damage.

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References

Muessel M, Berman N, Klein R . Early and specific expression of monocyte chemoattractant protein-1 in the thalamus induced by cortical injury. Brain Res. 2000; 870(1-2):211-21. DOI: 10.1016/s0006-8993(00)02450-1. View

Berman J, Guida M, Warren J, Amat J, Brosnan C . Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J Immunol. 1996; 156(8):3017-23. View

Morganti-Kossmann M, Satgunaseelan L, Bye N, Kossmann T . Modulation of immune response by head injury. Injury. 2007; 38(12):1392-400. DOI: 10.1016/j.injury.2007.10.005. View

Beni-Adani L, Gozes I, Cohen Y, Assaf Y, Steingart R, Brenneman D . A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther. 2000; 296(1):57-63. View

Glabinski A, Balasingam V, Tani M, Kunkel S, Strieter R, Yong V . Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. J Immunol. 1996; 156(11):4363-8. View

Flierl M, Stahel P, Beauchamp K, Morgan S, Smith W, Shohami E . Mouse closed head injury model induced by a weight-drop device. Nat Protoc. 2009; 4(9):1328-37. DOI: 10.1038/nprot.2009.148. View

Semple B, Kossmann T, Morganti-Kossmann M . Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab. 2009; 30(3):459-73. PMC: 2949152. DOI: 10.1038/jcbfm.2009.240. View

Stamatovic S, Shakui P, Keep R, Moore B, Kunkel S, van Rooijen N . Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J Cereb Blood Flow Metab. 2005; 25(5):593-606. DOI: 10.1038/sj.jcbfm.9600055. View

Muessel M, Klein R, Wilson A, Berman N . Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. Brain Res Mol Brain Res. 2002; 103(1-2):12-27. DOI: 10.1016/s0169-328x(02)00158-4. View

10.

Hausmann E, Berman N, Wang Y, Meara J, Wood G, Klein R . Selective chemokine mRNA expression following brain injury. Brain Res. 1998; 788(1-2):49-59. DOI: 10.1016/s0006-8993(97)01160-8. View

11.

Ghirnikar R, Lee Y, Eng L . Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res. 1998; 23(3):329-40. DOI: 10.1023/a:1022453332560. View

12.

Kossmann T, Stahel P, Lenzlinger P, Redl H, Dubs R, Trentz O . Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997; 17(3):280-9. DOI: 10.1097/00004647-199703000-00005. View

13.

Rancan M, Otto V, Hans V, Gerlach I, Jork R, Trentz O . Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J Neurosci Res. 2001; 63(5):438-46. DOI: 10.1002/1097-4547(20010301)63:5<438::AID-JNR1039>3.0.CO;2-P. View

14.

Kuziel W, Morgan S, Dawson T, Griffin S, SMITHIES O, Ley K . Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A. 1997; 94(22):12053-8. PMC: 23699. DOI: 10.1073/pnas.94.22.12053. View

15.

Schilling M, Strecker J, Schabitz W, Ringelstein E, Kiefer R . Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience. 2009; 161(3):806-12. DOI: 10.1016/j.neuroscience.2009.04.025. View

16.

Buttram S, Wisniewski S, Jackson E, Adelson P, Feldman K, Bayir H . Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia. J Neurotrauma. 2007; 24(11):1707-17. DOI: 10.1089/neu.2007.0349. View

17.

Hughes P, Allegrini P, Rudin M, Perry V, Mir A, Wiessner C . Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002; 22(3):308-17. DOI: 10.1097/00004647-200203000-00008. View

18.

Fuentes M, Durham S, Swerdel M, Lewin A, Barton D, Megill J . Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol. 1995; 155(12):5769-76. View

19.

Schroeter M, Jander S, Huitinga I, Witte O, Stoll G . Phagocytic response in photochemically induced infarction of rat cerebral cortex. The role of resident microglia. Stroke. 1997; 28(2):382-6. DOI: 10.1161/01.str.28.2.382. View

20.

Hermann D, Mies G, Hata R, Hossmann K . Microglial and astrocytic reactions prior to onset of thalamic cell death after traumatic lesion of the rat sensorimotor cortex. Acta Neuropathol. 2000; 99(2):147-53. DOI: 10.1007/pl00007418. View