Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development of dementia after TBI. Following the initial mechanical insult, TBI activates a cascade of molecular signaling events that can result in neurodegenerative sequelae, namely cognitive dysfunction. One of the most pronounced responses following TBI is the induction of multiple signaling mediators associated with neuroinflammation, consistently attributed to the activation of the innate immune system. Inflammation is a vital host response to injury, however excessive and unchecked propagation of inflammation can be deleterious to primarily unaffected tissues. Recent work in both humans and various animal models has shown that microglia, the brain's resident immune cells, can remain in an activated state for years after the initial insult. Despite consistent findings implicating the deleterious effects of chronically activated microglia in the brain, little is know about the role of the peripheral innate immune response and its interface with CNS tissues following TBI. Recent work has shown that cell surface expression of Ly6C and CCR2 is characteristic of an inflammatory subpopulation of bone marrow derived blood circulating monocytes. However, there is still a gap in the current knowledge as to the role and function of Ly6ChiCCR2+ monocytes in the propagation of TBI- induced pathology. The ultimate goal of this proposal is to elucidate the functional contribution of this cell subpopulation on TBI-induced neuroinflammation, as well as synaptic and cognitive dysfunction.
Aim 1. Will examine if genetic and pharmacological deletion of CCR2 signaling ameliorates TBI-induced synaptic and cognitive dysfunction. TBI will be induced using controlled cortical impact on both wild type and CCR2RFP/RFP mice. We will examine hippocampal-dependent cognitive function as well as homeostatic synaptic function, 28 days after injury. Preliminary studies indicate that CCR2 deletion abrogates TBI-induced hippocampal cognitive dysfunction compared to WT mice.
Aim 2. Will determine the temporal kinetics and inflammatory profile of TBI-induced Ly6ChiCCR2+ monocytes/macrophages into the brain parenchyma. TBI will be induced as in Aim 1 except using CX3CR1+/GFPCCR2+/RFP mice. Multiple time points following injury will be examined to include acute, subacute, and chronic phases. Preliminary data shows that 48 hours after injury, TBI-treated mice had a significant increase in macrophage infiltration and that a specific subset of those resembled resident microglia. Our studies will provide critical and novel information in regard to the contribution of peripheral macrophage accumulation in the pathogenicity of TBI-induced neuroinflammation and potentially a novel therapeutic target and optimal time point for its treatment.
Clinically, traumatic brain injury (TBI) is one of the most powerful environmental risk factors for the development of Alzheimer's disease and dementia. Emerging evidence suggest that neuroinflammation may play a pivotal role in TBI-induced neuropathology. However, a molecular mechanism for this association has not been identified. The proposed research employs (1) genetic approach to examine the contribution of CCR2-dependent signaling in the pathogenesis of TBI- induced neuroinflammatory response, (2) novel phase I pharmacological treatment that selectively inhibits CCR2 signaling, (3) a unique animal genotype that allows discrimination between resident (CX3CR1+/GFP) and peripheral (CCR2+/RFP) innate immune cells, and (4) a temporal design to elucidate the effects of TBI on innate immune response at acute, subacute, and chronic phases. Cumulatively, we will gain critical and novel information in regard to the contribution of peripheral macrophage accumulation in the pathogenicity of TBI-induced neuroinflammation and potentially a novel therapeutic target and optimal time point for its treatment.