Elsevier

Neuroscience

Volume 283, 26 December 2014, Pages 210-221
Neuroscience

Review
The role of the immune system in central nervous system plasticity after acute injury

https://doi.org/10.1016/j.neuroscience.2014.04.036Get rights and content

Highlights

  • Early immune activation after acute CNS injury might have neuroprotective effects.

  • Sustained inflammation profoundly shapes functional and structural plasticity within the CNS.

  • Modulation of the innate or adaptive immune responses represents a promising approach to treat acute CNS disorders.

Abstract

Acute brain injuries cause rapid cell death that activates bidirectional crosstalk between the injured brain and the immune system.

In the acute phase, the damaged CNS activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, thus bringing the inflammatory reaction to a close. In the chronic phase, a sustained immune activation has been described in many CNS disorders, and the degree of this prolonged response has variable effects on spontaneous brain regenerative processes. The challenge for treating acute CNS damage is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury.

Herein we have reviewed the available information regarding the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that are associated with intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization.

Introduction

Although considered for many years to be an immune privileged tissue, it is now well accepted that the CNS is engaged in an intense bidirectional communication with the immune system. The CNS physiologically controls peripheral immunity through complex humoral signaling and via the direct activation of neuronal pathways that include the hypothalamic–pituitary–adrenal axis and the autonomic nervous system (An et al., 2014). The hypothalamus normally suppresses the release of pro-inflammatory cytokines from T cells, monocytes and macrophages, while promoting the systemic release of anti-inflammatory cytokines, such as interleukin (IL)-10 (Chamorro et al., 2012). Similarly, the release of noradrenaline from the autonomic centers and peripheral organs (including the adrenal medulla, liver and spleen) induces a constitutive anti-inflammatory phenotype in circulating immune cells (Meisel et al., 2005). The immune system is in turn responsible for CNS development, surveillance and response to damage. In the developing brain, a large percentage of the processes underlying neurogenesis and dynamic pruning (i.e. the selective degeneration of whole or parts of dendrites and axon collaterals) is mediated by resident immune cells (Besedovsky and Rey, 2007, Boulanger, 2009). Later in adulthood, both resident and circulating immune cells function as primary guardians of the CNS and their sentinel duties contribute to the maintenance of normal homeostasis (Chamorro et al., 2012, Ousman and Kubes, 2012). Immune mechanisms are indeed responsible for the constant remodeling of neural circuits, memory consolidation, hippocampal long-term potentiation and neurogenesis in response to everyday environmental stimuli (Meisel et al., 2005, Yirmiya and Goshen, 2011).

After the occurrence of focal CNS damage, the lesioned area undergoes acute loss of function and neurodegeneration, which are later followed by a regenerative response aimed at restoring both structure and function. As the first line of defense in the CNS, the immune system provides the earliest responses against acute brain injury, which consist of both physical and chemical barriers created by innate immune cells (microglia/macrophages, neutrophils, and natural killer cells) and the complement system (Gelderblom et al., 2009). In this acute phase immune cells actively participate in the disruption of the blood–brain barrier (BBB), remodeling of the extracellular matrix (ECM), and activation of glial cells (reactive gliosis), while protecting neurons from increasing excitotoxicity, calcium release and free radicals (Dirnagl et al., 1999). This first intense systemic immune activation orchestrates the clearance of necrotic debris and the containment of the initial damage (Kamel and Iadecola, 2012).

The role of the immune system  during the regenerative phase within the CNS has yet to be fully elucidated. The CNS copes with injury and loss of function by enacting a variety of functional and structural changes in neural pathways and synapses, which are commonly referred to as CNS plasticity. In particular, the first phase of functional plasticity characterized by dendritic reorganization and axonal sprouting is followed by the second phase of structural neuroanatomical plasticity (e.g. generation of new neurons and vessels) ultimately leading to the formation of novel connections within the damaged brain (Wieloch and Nikolich, 2006). The components of both the innate and adaptive (T and B lymphocytes) immune responses profoundly shape functional and structural plasticity of the injured CNS by priming (or hindering) brain recovery via modulation of intrinsic growth properties and extrinsic growth-regulatory cues (Martino et al., 2011).

It has become increasingly clear that many of the events that characterize the acute neurodegeneration are linked (directly or indirectly) with the following regenerative phase, and that the immune activation within the CNS must be interpreted as a continuum between degenerative and reparative processes (Hermann and Chopp, 2012). In this review we focus on the role exerted by the innate and the adaptive immune responses in regulating CNS plasticity through the different phases of acute injury and subsequent recovery. In particular, we explore the ability of the immune system to modulate the initial BBB damage and glial activation, the following functional plasticity of neurons, and the final reparative regeneration of the injured CNS (Fig. 1). Since most of currently available evidence related to the innate and adaptive immune responses after damage has been derived from CNS focal-sterile injuries, we focus mainly on describing the pathophysiology and the evolution of acute (focal) damage after experimental ischemic stroke and spinal cord injury (SCI).

Section snippets

BBB damage and reactive gliosis

The BBB is composed of endothelial cells, pericytes, astrocytes and ECM that, together with neurons, are organized in a complex cellular system called the neurovascular unit (NVU) (Abbott et al., 2006). Upon ischemic brain injury, the NVU undergoes intense early changes that are comprised of the failure of ion pumps, overaccumulation of intracellular sodium and calcium, loss of membrane integrity and subsequent necrotic cell death. Release of damage-associated molecular patterns (DAMPs) from

Neuronal functional plasticity

Upon acute ischemic damage, neurons in the ischemic core (the region of low perfusion in which cells have lost their membrane potential terminally) release excitatory neurotransmitters (e.g. glutamate) and intracellular solutes (e.g. potassium) that trigger waves of peri-infarct depolarizations (PID) (Dreier, 2011). PID propagate from the lesion core toward the surrounding ischemic penumbra (the region where intermediate perfusion prevails along with partially preserved energy metabolism).

Reparative regeneration

Precursor cells of the main neurogenic zones within the adult brain, as well as local progenitors, have a major role in the recovery after CNS injury in mice (Butti et al., 2012). Classically, two fundamental brain regions, i.e. the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus, have been demonstrated to be responsible for the majority of neurogenesis in adult mammals (Doetsch, 2003). Upon ischemic injury, neurogenesis in these areas is rapidly increased and a pool

Conclusions

Damage to the central or peripheral nervous system results in the activation of complex immunological reactions that profoundly affect recovery after injury (Table 1). However, while the peripheral nervous system holds a certain degree of spontaneous regeneration after damage, the CNS retains a much lower regenerative capacity. While the myriad of factors governing the aforementioned phenomenon are not completely understood, the timing and pathophysiologic context of immune activation certainly

Acknowledgments

The authors thank Gillian Tannahill, Jayden A. Smith, Joshua D. Bernstock and Giulia Longoni for critically reviewing the article, and acknowledge the contribution of past and present members of the Marchetti and Pluchino laboratories, who have contributed to (or inspired) this manuscript.

This work was supported by grants from the UK National Multiple Sclerosis Society (NMSS; RG-4001-A1), the Italian Multiple Sclerosis Foundation (FISM; RG 2010/R/31), the Italian Ministry of Health (GR08/7) the

References (142)

  • T. Cohen et al.

    Interleukin 6 induces the expression of vascular endothelial growth factor

    J Biol Chem

    (1996)
  • R.M. Dijkhuizen et al.

    Correlation between tissue depolarizations and damage in focal ischemic rat brain

    Brain Res

    (1999)
  • U. Dirnagl et al.

    Pathobiology of ischaemic stroke: an integrated view

    Trends Neurosci

    (1999)
  • F. Doetsch

    A niche for adult neural stem cells

    Curr Opin Genet Dev

    (2003)
  • K.P. Doyle et al.

    Mechanisms of ischemic brain damage

    Neuropharmacology

    (2008)
  • C.T. Ekdahl et al.

    Brain inflammation and adult neurogenesis: the dual role of microglia

    Neuroscience

    (2009)
  • U. Heldmann et al.

    TNF-α antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain

    Exp Neurol

    (2005)
  • D.M. Hermann et al.

    Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation

    Lancet Neurol

    (2012)
  • J. Herz et al.

    Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions

    Neurobiol Dis

    (2012)
  • H. Hvilsted Nielsen et al.

    Stimulation of adult oligodendrogenesis by myelin-specific T cells

    Am J Pathol

    (2011)
  • H. Ishii et al.

    Th1 cells promote neurite outgrowth from cortical neurons via a mechanism dependent on semaphorins

    Biochem Biophys Res Commun

    (2010)
  • E.A. Jacobsen et al.

    Eosinophils: Singularly destructive effector cells or purveyors of immunoregulation?

    J Allergy Clin Immunol

    (2007)
  • M. Khalil et al.

    Brain mast cell relationship to neurovasculature during development

    Brain Res

    (2007)
  • H. Kobayashi et al.

    Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli

    Blood

    (2002)
  • H.F. Langer et al.

    Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis

    Blood

    (2010)
  • T.H. Lee

    Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells

    J Biol Chem

    (2002)
  • S. Nelissen et al.

    Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mastcell protease 4

    Neurobiol Dis

    (2014)
  • M. Pool et al.

    Molecular and cellular neuroscience

    Mol Cell Neurosci

    (2012)
  • N.J. Abbott et al.

    Astrocyte–endothelial interactions at the blood–brain barrier

    Nat Rev Neurosci

    (2006)
  • J.J. Alexander et al.

    Absence of functional alternative complement pathway alleviates lupus cerebritis

    Eur J Immunol

    (2007)
  • F. Aloisi et al.

    Lymphoid neogenesis in chronic inflammatory diseases

    Nat Rev Immunol

    (2006)
  • J.I. Alvarez et al.

    Glial influence on the blood brain barrier

    Glia

    (2013)
  • C. An et al.

    Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair

    Prog Neurobiol

    (2014)
  • A. Arvidsson et al.

    Neuronal replacement from endogenous precursors in the adult brain after stroke

    Nat Med

    (2002)
  • M. Asahi et al.

    Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia

    J Neurosci

    (2001)
  • M. Bacigaluppi et al.

    Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms

    Brain

    (2009)
  • S. Baldus et al.

    Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration

    J Clin Invest

    (2001)
  • Q. Bao Dang et al.

    High-density lipoproteins limit neutrophil-induced damage to the blood–brain barrier in vitro

    J Cereb Blood Flow Metab

    (2013)
  • H. Beck et al.

    Angiogenesis after cerebral ischemia

    Acta Neuropathol

    (2009)
  • J.L. Bennett et al.

    Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis

    J Immunol

    (2009)
  • S. Bourbié-Vaudaine et al.

    Dendritic cells can turn CD4+ T lymphocytes into vascular endothelial growth factor-carrying cells by intercellular neuropilin-1 transfer

    J Immunol

    (2006)
  • F.H. Brennan et al.

    Complement activation in the injured central nervous system: another dual-edged sword?

    J Neuroinflamm

    (2012)
  • E. Butti

    Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity

    Brain

    (2012)
  • E. Cacci et al.

    In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia

    Glia

    (2008)
  • S.T. Carmichael

    Cellular and molecular mechanisms of neural repair after stroke: making waves

    Ann Neurol

    (2006)
  • A. Chamorro et al.

    The immunology of acute stroke

    Nar Rev Neurol

    (2012)
  • Y. Chu et al.

    Enhanced synaptic connectivity and epilepsy in C1q knockout mice

    Proc Natl Acad Sci USA

    (2010)
  • J.A.M. Coull et al.

    BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

    Nature

    (2005)
  • M. Cusimano et al.

    Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord

    Brain

    (2012)
  • J.P. Dreier

    The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease

    Nat Med

    (2011)
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