Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury

Tweedie, David; Karnati, Hanuma Kumar; Mullins, Roger J.; Pick, Chaim G.; Hoffer, Barry J.; Goetzl, Edward J.; Kapogiannis, Dimitrios; Greig, Nigel H.

doi:10.7554/elife.55827

Cited by 32 publications

(21 citation statements)

References 106 publications

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“…The goal of pre-clinical studies is to provide a spectrum of knowledge generated from multiple, distinct pre-clinical models that encompass the full range of injuries from mild to severe TBI (Katz & Molina, 2018;Mychasiuk et al, 2014;Shultz et al, 2017;Siebold et al, 2018). For example, a recent large-scale proteomic study of closed head weigh drop TBI in mice reveals distinct C/C protein dynamics compared to our study with no reported increase in IL-1β, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, or CCL3 PI (Tweedie et al, 2020). Indeed, IL-6 was chronically downregulated in this diffuse injury model highlighting the importance of generating data from multiple pre-clinical models of TBI.…”

Section: Con Clus Ionmentioning

confidence: 75%

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

Nieves

Furmanski

Doughty

2020

J of Neuroscience Research

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Traumatic brain injury is a leading cause of mortality and morbidity in the United States. Acute trauma to the brain triggers chronic secondary injury mechanisms that contribute to long-term neurological impairment. We have developed a single, unilateral contusion injury model of sensorimotor dysfunction in adult mice. By targeting a topographically defined neurological circuit with a mild impact, we are able to track sustained behavioral deficits in sensorimotor function in the absence of tissue cavitation or neuronal loss in the contused cortex of these mice. Stereological histopathology and multiplex enzyme-linked immunosorbent assay proteomic screening confirm contusion resulted in chronic gliosis and the robust expression of innate immune cytokines and monocyte attractant chemokines IL-1β, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, and CCL3 in the contused cortex. In contrast, the expression of neuroinflammatory proteins with adaptive immune functions was not significantly modulated by injury. Our data support widespread activation of innate but not adaptive immune responses, confirming an association between sensorimotor dysfunction with innate immune activation in the absence of tissue or neuronal loss in our mice.

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Section: Con Clus Ionmentioning

confidence: 75%

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

Nieves

Furmanski

Doughty

2020

J of Neuroscience Research

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“…In previous studies NADPH oxidase activity increases within 1 h in neurons and a second increase is seen around 24–96 h after trauma. Interestingly, CCL5 mRNA is upregulated in the cortex immediately after injury and decreases 24–48 h after brain trauma which is parallel to elevated OS in brain tissue [ 10 , 11 , 23 ]. Many studies have shown the correlation between CCL5 and the NADPH oxidase response in immune cells' priming processes [ 24 ]; moreover NADPH oxidase is associated with CCL5 activation [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury

Yen

Hsieh

et al. 2021

Redox Biology

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Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C–C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor – N -acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1–3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.

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“…Increasing our understanding of the circadian and immune system response to injury can help to elucidate the complex outcomes of TBI and may shed light on more innovative treatments. For example, recent work in inflammation has found mouse cortical cytokines and chemokines show temporal expression pattern changes from as soon as 8 h following a single closed head injury to as long as 30 days post post-TBI ( Tweedie et al, 2020 ). Further characterization of the specific impairments to the circadian system can also advance understanding of TBI outcomes and help to better inform treatment.…”

Section: Discussionmentioning

confidence: 99%

The interaction of the circadian and immune system: Desynchrony as a pathological outcome to traumatic brain injury

Yamakawa

Brady

Sun

et al. 2020

Neurobiology of Sleep and Circadian Rhythms

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Traumatic brain injury (TBI) is a complex and costly worldwide phenomenon that can lead to many negative health outcomes including disrupted circadian function. There is a bidirectional relationship between the immune system and the circadian system, with mammalian coordination of physiological activities being controlled by the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN receives light information from the external environment and in turn synchronizes rhythms throughout the brain and body. The SCN is capable of endogenous self-sustained oscillatory activity through an intricate clock gene negative feedback loop. Following TBI, the response of the immune system can become prolonged and pathophysiological. This detrimental response not only occurs in the brain, but also within the periphery, where a leaky blood brain barrier can permit further infiltration of immune and inflammatory factors. The prolonged and pathological immune response that follows TBI can have deleterious effects on clock gene cycling and circadian function not only in the SCN, but also in other rhythmic areas throughout the body. This could bring about a state of circadian desynchrony where different rhythmic structures are no longer working together to promote optimal physiological function. There are many parallels between the negative symptomology associated with circadian desynchrony and TBI. This review discusses the significant contributions of an immune-disrupted circadian system on the negative symptomology following TBI. The implications of TBI symptomology as a disorder of circadian desynchrony are discussed.

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Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury

Cited by 32 publications

References 106 publications

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury

The interaction of the circadian and immune system: Desynchrony as a pathological outcome to traumatic brain injury

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