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

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.

Posttraumatic Invasion of Monocytes across the Blood—Cerebrospinal Fluid Barrier

“…The influx of these inflammatory cells is driven by monocyte chemoattractants, such as CCL2, whose synthesis is rapidly increased in the injured cortex (Semple et al, 2010a;Szmydynger-Chodobska et al, 2010). In the present study, we demonstrated that neurotrauma also results in a rapid increase in production of CCL2 by the lateral ventricle CP located ipsilaterally to injury.…”

Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity

“…Mice deficient in CXC receptor 2 which interacts with chemokines CXCL8, CXCL1 and CXCL2 and mediates the neutrophil transmigration across the BBB were reported to demonstrate significant attenuation of neutrophil infiltration, reduced tissue damage and neuronal loss, especially in the delayed phase post injury (Semple et al, 2010a). In a similar study, deletion of monocyte chemokine CCL2 gene resulted in improved neurological function, delayed reduction in lesion volume and macrophage accumulation (Semple et al, 2010b). Both the latter studies support the notion that late inhibition of leukocyte recruitment in TBI may be beneficial for the extent of brain trauma and the clinical outcome.…”

The current state of biomarkers of mild traumatic brain injury

“…Increased concentrations of inflammatory proteins, such as IL-6, IL-8, and IL-10, in the CSF following injury have been reported in many studies (87)(88)(89)(90)(91)(92)(93). It is unclear if this immune response is a result of local production of immune mediators or leakage of these proteins across a compromised BBB.…”