Insights into the protective role of immunity in neurodegenerative disease

Insights into the protective role of immunity in neurodegenerative disease

Microglia are the resident macrophages of the CNS exerting protective functions through phagocytosis of pathogens and cellu‐lar debris. In neurodegenerative diseases, microglia play a role in removing apoptotic cells and protein aggregates. In the early stages of Alzheimer’s disease (AD), the demolition of protein aggregates is ful fi lled through the release of proteolytic enzymes, such as matrix metalloproteinases. Phagocytosis of debris then occurs thanks to speci fi c receptors, such as the scavenger receptors. If, initially, these mechanisms are sufficient to protect neuronal homeostasis, the persistent deposition of Aβ may favor a detrimental in fl ammation (Cappellano et al., 2013).

In addition to phagocytosis, microglia can exert neuroprotective functions through the production of anti‐in fl ammatory cytokines, chemokines, and neurotrophic factors, stimulating tissue repair and neuron survival. For example, concentration of growth arrest spe‐ci fi c 6 (Gas6) (Figure 1), an anti‐in fl ammatory molecule involved in the macrophage‐microglia network, was found to be increased in early AD patients compared to age matched controls, and such an increase was also shown to confer protection against cognitive decline in patients who were prospectively followed‐up over one year from AD diagnosis (Sainaghi et al., 2016).

A potential neuroprotective activity has also been acknowledged to astrocytes, since it was shown that they can both promote cell debris degradation and inhibit adaptive response suppressing lym‐phocytes activation and proliferation. Astrocytes are the most nu‐merous glial population.ey play immune functions recognizing pathogens and producing cytokines and chemokines, and neuronal supporting function by producing growth factors, adjusting ex‐tracellular fl uids, and conditioning synaptic transmission. Recent studies in murine models have shown that astrocytes may play a key role in various protective mechanisms against immune‐mediated damage (Colombo and Farina, 2016). One of the protective mech‐ anisms is carried out by the glycoprotein gp130, which transduces survival signals for glial cells and acts in inflammation switching o ff. Another mechanism is mediated by transforming growth fac‐tor‐β (TGF‐β), a pleiotropic cykokine showing anti‐in fl ammatory properties. TGF‐β can inhibit the production of in fl ammatory me‐diators by astrocytes, the recruitment of T cells and, ultimately, the immune‐mediated damage, through the inhibition of the pro‐in‐fl ammatory NF‐κB pathway (Figure 1). Finally, astrocytes can turn off also the adaptive response, being able to induce apoptosis in T‐cells, favoring their elimination through Fas‐Fas ligand pathway.

Cytokines are an heterogeneous group of small secreted signal‐ing molecules important for inter‐ and intracellular communication during the immune response. They also contribute to maintenance of neural balance, neurogenesis, cell proliferation, migration and apoptosis. Cytokines can play, alternately, pro‐inflammatory or an‐ti‐inflammatory roles. Interleukin‐1 (IL‐1) receptor antagonist and IL‐10 display a clear anti‐in fl ammatory function, conferring neuro‐protection in both AD and Parkinson’s disease (PD): they attenuate microglia activation and inhibit release of other pro‐inflammatory cytokines (Cappellano et al., 2013). Other cytokines can perform a protective activity in neurodegenerative disease. This is the case of IL‐4 and TGF‐β: the former inhibitsin vitrothe production of pro‐in‐flammatory cytokines, andin vivoappears to stimulate a quiescent state of glia while facilitating phagocytosis (Figure 1).e latter can protect neurons through the decrease of IL‐17 production and facili‐tate the removal of amyloid plaques in AD (Zheng et al., 2016). Even cytokines with a predominantly pro‐inflammatory action, such as tumor necrosis factor‐ α (TNF‐α), IL‐1 and IL‐6, were reported to display anti‐inflammatory activity in peculiar contexts (Cappellano et al., 2013). TNF‐α was proven e ff ective in protecting hippocampal neurons from excitotoxicity‐mediated damage in animal models of neurodegeneration; In AD animal models, IL‐1 can reduce the accu‐mulation of amyloid plaques favoring its degradation or limiting its production; IL‐6 may stimulate an activated phenotype of microglia, inclined to the elimination of amyloid plaques, rather than to stim‐ulation of the in fl ammatory state. A further example is displayed by osteopontin (OPN), a pro‐in fl ammatory cytokine which was shown to be involved in several neurodegenerative diseases (Carecchio and Comi, 2011). Robust evidence points to a detrimental role of OPN in multiple sclerosis, since it was shown that polymorphic variants of its gene are associated with faster disease progression, but also that increased levels of circulating OPN are associated with disease re‐lapses (Comi et al., 2012). A similar scenario was detected in AD: AD patients showed higher OPN concentration in the cerebrospinal fl uid compared to matched controls, and such increase was more evident in patients showing faster cognitive decline (Carecchio and Comi, 2011). On the contrary, evidence on the role of OPN in PD is somehow con‐fl icting, since both detrimental and protective functions were detected (Carecchio and Comi, 2011) (Figure 1). Recent reports suggest that the pleiotropic activity of this protein might depend, at least in part, by post‐translational modi fi cations (Boggio et al., 2016).

Cytokine production occurs under the control of several cellular pathways, including MAPK, NF‐κB, and peroxisome prolifera‐tor activated receptor γ (PPAR‐γ) pathways, the latter related to a strong anti‐inflammatory activity, consisting in suppression of in fl ammatory genes expression and blockade of in fl ammatory cy‐tokines production (Cappellano et al., 2013). Conversely, NF‐κB pathway was shown to be primarily involved in pro‐in fl ammatory responses, and its inhibition has been proved useful in reducing detrimental neuroin fl ammation (Colombo and Farina, 2016).

The role of the complement system is mainly regarded as pro‐in fl ammatory, since it favors the recognition of pathogens by phagocytic cells and stimulates chemotaxis. Nonetheless, it was also shown that C3a can provide protection against glutamate mediated excitotoxicity in murine models of neurodegeneration (Cappellano et al., 2013). Furthermore, inhibition of C5, C3 and C1q may favor amyloid β deposition (Cappellano et al., 2013). In this context, the anti‐inflammatory activity of complement is expressed through the inhibition of pro‐in fl ammatory cytokines, removal of apoptotic cells and stimulation of neuronal survival (Cappellano et al., 2013).

Figure 1e main players of neuroprotective in fl ammation.

In the CNS, the adaptive immune response is essentially orches‐trated by CD4+lymphocytes. CD4+cells can exert pro‐in fl ammatory functions, as in the case of Type 1 and Type 17 Helper cells (1 and17), or alternatively anti‐in fl ammatory or regulatory func‐tions, when Type 2 Helper cells (Th2) or T‐reg cells are involved (Figure 1). In fi ltration of CD4+T‐reg cells confers neuroprotection in AD through the modulation of microglia, especially inhibiting the production of pro‐inflammatory factors. The switch to an anti‐in‐ fl ammatory phenotype is essentially regulated by cytokines (Figure 1). Findings from AD animal models indicate that IL‐2 is e ff ective in inducing expansion of T‐reg cells.ese cells are able, in turn, to stimulate phagocytosis of amyloid plaques by microglial cells, with a maximum effect occurring in the early stages of disease, when cognitive functions can still be restored.e concept of a bene fi cial role of the immune system in coping to external/internal insults and favoring neuroplasticty was previously de fi ned as “protective auto‐immunity”. According to this notion, aging of the immune system would impair its ability to protect the CNS, thus favoring neurode‐generation (Schwartz and Raposo, 2014).

A protective activity is not an exclusive prerogative of T‐lympho‐cytes. Indeed, in immunode fi cient AD murine models, the decrease not only of T‐lymphocytes, but also of B‐lymphocytes and natural killer cells can favor a detrimental loop, driven by the overproduc‐tion of pro‐in fl ammatory cytokines and concomitant reduction of phagocytic capacity of microglia (Zheng et al., 2016).

Another important aspect of the adaptive immune response is the presence of receptors for neurotransimetters on T cells.is is of particular relevance in PD, since dopaminergic treatment was shown to modulate patients’ T cell proteome (Alberio et al., 2012), and dopamine receptor expression on patients’ T cells was associ‐ated with motor dysfunction measured by the Uni fi ed Parkinson’s Disease Rating Scale (Kustrimovic et al., 2016).

Indeed, a fine and targeted modulation of immunity might represent an effective therapeutic strategy for neurodegenerative diseases, especially considering that previous attempt to broadly counteract neuroin fl ammation with non‐steroidal anti‐in fl amma‐tory drugs (NSAIDs) have yielded disappointing results (Cappellano et al., 2013). Consistently, studies selectively targeting innate and/ or adaptive immunity are ongoing. As regards innate immunity, one strategy may involve up‐regulation of microglial phagocytic capacity, through the administration of colony‐stimulating factors. Granulocyte macrophage colony stimulating factor (GM‐CSF) is increased in patients with rheumatoid arthritis, a disease confer‐ring some protection from AD development.e administration of GM‐CSF in AD mice was e ff ective in reducing beta amyloid depo‐sition and protecting hippocampal synapses (Boyd et al., 2010). En‐couraging results were obtained also in humans: in cancer patients undergoing hematopoietic cell transplantation, supportive care with GM‐CSF induced an improvement of cognitive performance (Jim et al., 2012). Such preliminary observations led the recent launch of a phase 2 trial on GM‐CSF use in AD. On the side of adaptive im‐munity, clinical trials with active or passive immunization strategies have been conducted, especially targeting AD.e fi rst and second era of AD immunotherapy did not meet the expectations.e fi rst vaccination protocol failed due to immunologic side e ff ects, while in the second course of trials it is likely that the target population was in a too advanced disease phase to show signi fi cant bene fi t.e next step consisted in enrolling very early AD patients, in order to act when neurodegeneration was in its initial phases. Some prelim‐inary results are promising and the strategy of anticipating drug administration has a strong rationale. Furthermore, clinical trials with immunotherapy targeting alpha‐synuclein in PD are ongoing.

Cristoforo Comi＊, Giacomoondo

Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy (Comi C, Tondo G) Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy (Comi C)

＊Correspondence to: Cristoforo Comi, M.D., Ph.D., comi@med.uniupo.it.

Accepted:2017-01-05

orcid: 0000-0002-6862-9468 (Cristoforo Comi)

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How to cite this article:Comi C, Tondo G (2017) Insights into the protective role of immunity in neurodegenerative disease. Neural Regen Res 12(1):64-65.

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