Highlights
- •Time course of M1/M2 cytokine's gene expression and protein levels in the hippocampus
- •There are heterogeneous expressions of both the M1 and M2 phenotypes early after TBI.
- •Initially, a large and quick M1 response overpowers the M2 phenotypes after TBI.
Abstract
Traumatic brain injury (TBI) elicits complex inflammatory assets (M1 and M2 responses)
in the brain that include the expression of various cytokines/chemokines and the recruitment
of blood cells, contributing secondary injury cascades (SIC), and also recovery processes.
The modulation of such inflammatory assets might be a therapeutic option following
TBI. The present study assesses a temporal profile of various molecular markers of
M1 and M2 response in the hippocampus after TBI. Following a unilateral controlled
cortical impact (CCI) on young rats, hippocampal tissues of each brain were harvested
at 2, 4, 6, 10, and 24 h post trauma. Including shams (craniotomy only), half of the rats were assessed for
gene expression and half for the protein of various markers for M1 [interferon-gamma
(IFNγ), tumor necrosis factor-α (TNFα), interleukin (IL)-1-β (IL-1β), and IL-6] and
M2 [IL-4, IL-10, IL-13, arginase 1 (Arg1), YM1, FIZZ1, and mannose receptor C-1 (MRC1)]
responses. Analysis revealed that molecular markers of M1 and M2 responses have heterogeneous
injury effects in the hippocampus and that “time-post-injury” is an important factor
in determining inflammation status. With the heterogeneous gene expression of pro-inflammatory
cytokines, M1 response was significantly elevated at 2 h and declined at 24 h after TBI, however, their levels remained higher than the sham rats. Except IFNγ,
proteins of M1 cytokines were significantly elevated in the first 24 h, and peaked between 2–6 h [TNFα (2 h), IL-1β (6 h), and IL-6 (4–6 h)]. With the heterogeneous relative gene expression of Arg1, YM1, FIZZ1, and MRC1,
levels of M2 cytokines were peaked at 24 h post TBI. IL-10 and IL-13 expression appeared biphasic in the first 24 h. Protein values of IL-4 and IL-13 peaked at 24 h and IL-10 at 6 h post injury. Results suggest that the M1 response rises rapidly after injury and
overpowers the initial, comparatively smaller, or transient M2 response. A treatment
that can modulate inflammation, reduce SIC, and improve recovery should be initiated
early (within 10 h) after TBI.
Abbreviations:
TBI (traumatic brain injury), SIC (secondary injury cascades), CCI (controlled cortical impact), M1 (classical activation of microglia/macrophages), M2 (alternative activation of microglia/macrophages), qRT-PCR (quantitative real-time reverse transcription-polymerase chain reaction), rRNA (ribosomal ribonucleic acid), cDNA (complementary deoxyribonucleic acid), ELISA (enzyme-linked immunosorbent assay), Arg-1 (arginase-1), MRC-1 (mannose receptor C type-1), FIZZ-1 (found in inflammatory zone protein (Resistin-like molecule alpha)), IFNγ (interferon-gamma), TNFα (tumor necrosis factor-α), IL-1β (interleukin-1-β)Keywords
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References
- Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures.Glia. 2013; 61: 1698-1711
- Inflammation in neurodegenerative diseases.Immunology. 2010; 129: 154-169
- Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury.Neuroscience. 2009; 158: 1112-1121
- Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury.Free Radic. Biol. Med. 2008; 45: 443-452
- A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI.J. Neurotrauma. 2008; 25: 513-526
- Dose- and time-dependent neuroprotective effects of Pycnogenol following traumatic brain injury.J. Neurotrauma. 2013; 30: 1542-1549
- A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma.Free Radic. Biol. Med. 2014; 77: 21-29
- The systemic response to brain injury and disease.Brain Behav. Immun. 2012; 26: 534-540
- Special issue commentary: the changing face of inflammation in the brain.Mol. Cell. Neurosci. 2013; 53: 1-5
- Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS.J. Neurosci. 2003; 23: 7922-7930
- IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease.FASEB J. 2008; 22: 2843-2852
- Immunomagnetic enrichment and flow cytometric characterization of mouse microglia.J. Neurosci. Methods. 2013; 219: 176-182
- How do we define inflammation?.Praxis. 1994; 83: 1343-1347
- TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement.Nat. Neurosci. 2013; 16: 1773-1782
- Dynamic changes in N-methyl-d-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 5117-5122
- Microglia-mediated neurotoxicity: uncovering the molecular mechanisms.Nat. Rev. Neurosci. 2007; 8: 57-69
- Differential induction of interleukin-1beta and tumour necrosis factor-alpha may account for specific patterns of leukocyte recruitment in the brain.Brain Res. 2002; 958: 89-99
- Review: activation patterns of microglia and their identification in the human brain.Neuropathol. Appl. Neurobiol. 2013; 39: 3-18
- Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes.J. Immunol. 2000; 164: 3862-3869
- Neuronal plasticity and cellular immunity: shared molecular mechanisms.Curr. Opin. Neurobiol. 2001; 11: 568-578
- Inflammatory neurodegeneration and mechanisms of microglial killing of neurons.Mol. Neurobiol. 2010; 41: 242-247
- Broad expression of Toll-like receptors in the human central nervous system.J. Neuropathol. Exp. Neurol. 2002; 61: 1013-1021
- Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells.Mol. Cell. Neurosci. 2006; 31: 149-160
- Polarization of macrophages and microglia in inflammatory demyelination.Neurosci. Bull. 2013; 29: 189-198
- The cytokine temporal profile in rat cortex after controlled cortical impact.Front. Mol. Neurosci. 2012; 5: 6
- Multiple defects of immune cell function in mice with disrupted interferon-gamma genes.Science. 1993; 259: 1739-1742
- Repertoire of microglial and macrophage responses after spinal cord injury.Nat. Rev. Neurosci. 2011; 12: 388-399
- Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages.J. Neurosci. 2011; 31: 9910-9922
- ‘Neuroinflammation’ differs categorically from inflammation: transcriptomes of Alzheimer's disease, Parkinson's disease, schizophrenia and inflammatory diseases compared.Neurogenetics. 2014; 15: 201-212
- Neuropsychological sequelae of diffuse traumatic brain injury.Brain Inj. 2005; 19: 101-108
- Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia.Neurosci. Res. 2012; 73: 122-132
- CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice.Glia. 2013; 61: 827-842
- Microglial reaction in the rat cerebral cortex induced by cortical spreading depression.Brain Pathol. 1993; 3: 11-17
- Long-term intracerebral inflammatory response after traumatic brain injury.Forensic Sci. Int. 2004; 146: 97-104
- Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices.Glia. 2013; 61: 813-824
- The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain.J. Neurosci. 1989; 9: 4416-4429
- Alternative activation of macrophages.Nat. Rev. Immunol. 2003; 3: 23-35
- Changing face of microglia.Science. 2010; 330: 783-788
- Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells.Prog. Neurobiol. 2008; 84: 211-233
- Proliferation of microglia and astrocytes in the dentate gyrus following entorhinal cortex lesion: a quantitative bromodeoxyuridine-labelling study.Eur. J. Neurosci. 1999; 11: 3359-3364
- Traumatic brain injury induces macrophage subsets in the brain.Eur. J. Immunol. 2013; 43: 2010-2022
- Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia.Stroke. 2012; 43: 3063-3070
- Secreted protein lipocalin-2 promotes microglial M1 polarization.FASEB J. 2013; 27: 1176-1190
- Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice.PLoS One. 2012; 7: e41892
- Effect of inflammatory cytokines on major histocompatibility complex expression and differentiation of human neural stem/progenitor cells.Stem Cells. 2008; 26: 2444-2454
- Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord.J. Neurosci. 2009; 29: 13435-13444
- Differences in angiogenic potential of classically vs alternatively activated macrophages.Immunobiology. 1997; 197: 478-493
- Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain.J. Neurosci. 2007; 27: 2596-2605
- Tracking the silent epidemic and educating the public: CDC's traumatic brain injury-associated activities under the TBI Act of 1996 and the Children's Health Act of 2000.J. Head Trauma Rehabil. 2005; 20: 196-204
- Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke.Nat. Med. 2009; 15: 192-199
- Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention.J. Pharmacol. Exp. Ther. 2003; 304: 1-7
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method.Methods. 2001; 25: 402-408
- Systemic inflammatory response following acute traumatic brain injury.Front. Biosci. 2009; 14: 3795-3813
- Moderate and severe traumatic brain injury in adults.Lancet Neurol. 2008; 7: 728-741
- The chemokine system in diverse forms of macrophage activation and polarization.Trends Immunol. 2004; 25: 677-686
- Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration.Mult. Scler. 2011; 17: 2-15
- The many faces of macrophage activation.J. Leukoc. Biol. 2003; 73: 209-212
- Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.Science. 2005; 308: 1314-1318
- Defining “neuroinflammation”.Ann. N. Y. Acad. Sci. 2008; 1139: 318-330
- Phenotype and secretory responses to oxidative stress in microglia.Dev. Neurosci. 2013; 35: 241-254
- Three-dimensional confocal analysis of microglia/macrophage markers of polarization in experimental brain injury.J. Vis. Exp. 2013; : e50605https://doi.org/10.3791/50605
- Neurodegeneration and inflammation in Parkinson's disease.Parkinsonism Relat. Disord. 2012; 18: S207-S209
- Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion.Brain Behav. Immun. 2010; 24: 540-553
- NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia.J. Biol. Chem. 2004; 279: 1415-1421
- Inflammation after trauma: microglial activation and traumatic brain injury.Ann. Neurol. 2011; 70: 374-383
- Neuroinflammation and synaptic loss.Neurochem. Res. 2012; 37: 903-910
- CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion.J. Neurosci. 2004; 24: 8500-8509
- A brief survey of the history of inflammation. 1978.Agents Actions. 1994; 43: 86-90
- Cholinergic control of inflammation.J. Intern. Med. 2009; 265: 663-679
- Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.Neuron. 2012; 74: 691-705
- Neuroprotective effect of Pycnogenol(R) following traumatic brain injury.Exp. Neurol. 2013; 239: 183-191
- What is “inflammation”? Are we ready to move beyond Celsus?.Br. J. Sports Med. 2004; 38: 248-249
- Diverse activation of microglia by chemokine (C–C motif) ligand 2 overexpression in brain.J. Neuroinflammation. 2013; 10: 86
- Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.PLoS Med. 2009; 6: e1000113
- Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’.J. Pathol. 2013; 229: 332-346
- Genetic and histologic evidence implicates role of inflammation in traumatic brain injury-induced apoptosis in the rat cerebral cortex following moderate fluid percussion injury.Neuroscience. 2010; 171: 1273-1282
- Calcium-mediated processes in neuronal degeneration.Ann. N. Y. Acad. Sci. 1994; 747: 140-161
- Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens.Nat. Rev. Immunol. 2006; 6: 318-328
- The classical complement cascade mediates CNS synapse elimination.Cell. 2007; 131: 1164-1178
- Toll-like receptor 2-mediated alternative activation of microglia is protective after spinal cord injury.Brain. 2014; 137: 707-723
- Intracranial injection of gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers A beta in APP/PS1 mice along a different time course than anti-A beta antibodies.J. Neurosci. 2013; 33: 9684-9692
- Neuroinflammatory phenotype in early Alzheimer's disease.Neurobiol. Aging. 2013; 34: 1051-1059
- Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?.J. Neurosci. Res. 2005; 79: 231-239
- Microglial responses after ischemic stroke and intracerebral hemorrhage.Clin. Dev. Immunol. 2013; 2013: 746068
- Macrophagic and microglial responses after focal traumatic brain injury in the female rat.J. Neuroinflammation. 2014; 11: 82
- The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain.Arch. Immunol. Ther. Exp. 2012; 60: 251-266
- A new role for interferon gamma in neural stem/precursor cell dysregulation.Mol. Neurodegener. 2011; 6: 18
- Microglia/macrophage polarization dynamics in white matter after traumatic brain injury.J. Cereb. Blood Flow Metab. 2013; 33: 1864-1874
- Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice.J. Neuroinflammation. 2014; 11: 127
- Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders.J. Neurochem. 2009; 108: 1343-1359
- Diverse inflammatory responses in transgenic mouse models of Alzheimer's disease and the effect of immunotherapy on these responses.ASN Neuro. 2011; 3: 249-258
- The systemic and local acute phase response following acute brain injury.J. Cereb. Blood Flow Metab. 2002; 22: 318-326
- Interleukin-4, interleukin-10, and interleukin-1-receptor antagonist but not transforming growth factor-beta induce ramification and reduce adhesion molecule expression of rat microglial cells.J. Neurosci. Res. 2002; 68: 579-587
- Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia.Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15769-15774
Article info
Publication history
Published online: June 29, 2015
Accepted:
June 26,
2015
Received in revised form:
June 10,
2015
Received:
March 16,
2015
Identification
Copyright
© 2015 Published by Elsevier Inc.
