ReviewThe role of the immune system in central nervous system plasticity after acute injury
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
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These authors contributed equally.