A tale of two systems – Gates that guard the CNS

By Siddharth Krishnan, PhD Candidate, The University of Manchester

The nervous and immune systems have been historically perceived as disparate entities, separated by the blood-brain barrier (BBB) with little interaction between the two1,2. Consequently, this shaped our perception of the central nervous system (CNS) as possessing a dampened2 and compartmentalised immune system with resident cells such as astrocytes assuming immune roles such as antigen presentation3. However, the role of signalling molecules of the immune system such as cytokines in CNS function4–7 and vice-versa, i.e. the role of classical neurotransmitters in modulating immune function8–11 has contributed to a paradigm shift in our understanding of our understanding of the two systems. This has in no small part been fuelled by evolving technology and analyses routes, crucially multi-parametric flow cytometry and high dimensional, automated analysis12–15 as well as the unparalleled transcriptomic resolution at the single-cell level16–20. This article will endeavour to briefly discuss some of the key questions confronting our understanding of the interplay of these two systems.

Why the cross-talk?

The fundamental premise of neuro-immunology, i.e., the cross-talk between the two systems begs reason to the evolutionary advantage of this trait. In this context, studies have implicated  interferon-γ (IFN- γ) in modulating social behaviour4, CX3CR1+ monocytes in learning-dependent dendritic spine formation21 and hypothalamic lipolysis driving adaptive immunity in response to infection-induced tumour necrosis factor-α (TNF-α)22. These suggest pathogens as being key drivers in the evolution of immune signals shaping CNS function in order to curtail their spread through the induction of social withdrawal and sickness behaviour23. This idea is reinforced by other data demonstrating the importance of sympathetic neural signals in driving immune responses to infection through the induction of tissue-protective programmes in gut macrophages24,25 or inflammation, by modulating macrophage transcriptional programmes 8,26,27. The latter has spurred progress in our appreciation of trained innate immunity28–30 and role of the nervous system in imparting this “education” to immune cells31,32. Thus, it can be interpreted that the neural input to the immune system serves to tune and elicit a highly coordinated immune response to curtail and eliminate the pathogen or inflammation and promote tissue repair.

Gates that guard the CNS

Given this intimate interaction that exists between the CNS and the immune system, another key question is the route of entry and exit from CNS adopted by immune cells. Whilst previously thought that the immune privilege of the CNS1,2 implied the absence of lymphatic vessels, recent research has uncovered the existence of lymphatic vessels in the dural sinuses carrying cerebrospinal fluid (CSF)-derived immune cells and fluid33. Studies investigating immune changes in response to CNS damage in ischaemic stroke have also discovered alternative routes of CNS entry wherein the recruitment of pro-inflammatory gdT cells secreting interleukin-17 (IL-17) to the ischaemic brain occurs through the leptomeninges34,35 whilst neutrophils are recruited via a breached BBB post-stroke36,37. This has led to the notion that route of entry is dependent upon on the anti-inflammatory status of the infiltrating cell as contexts of stroke and spinal cord injury have demonstrated that the recruitment of beneficial (reparative) monocytes occurs via the choroid plexus38,39. In addition to immune cells that infiltrate the CNS during homeostasis and disease, like most other tissues, the CNS is also endowed with populations of tissue-resident macrophages like microglia, perivascular and meningeal macrophages that are embryonically seeded from yolk sac40–42. Further, the meningeal space has also been shown to harbour a population of type 2 innate lymphoid cells (ILC2) that have been shown to be important in mediating tissue repair through their production of type 2 cytokines in an IL-33-dependent manner post-injury6,43. Therefore, the concept of immune privilege has to be reformed to be relative, more applicable to the parenchyma and much less at the frontiers of the CNS, common to both to innate and adaptive arms and one that is compromised during inflammation 44.


Perturbations in neuro-immune interactions

The blurring of the boundaries between the CNS and the immune system has meant that diseases affecting either system have an inevitable impact on the other. Diseases affecting systemic immunity such as infections or autoimmune disease such as multiple sclerosis (MS) can also significantly impact CNS function including the physical damage of neuronal networks as well as cognition. This occurs predominantly through the propagation of neuroinflammation as a consequence of both myeloid and lymphoid cells from the periphery infiltrating the CNS21,45–47. Specifically, in experimental models of MS, experimental autoimmune encephalomyelitis (EAE), it is thought that development of disease is facilitated by the presentation of myelin-derived antigens by antigen presenting cells to T cells at CNS interfaces and secondary lymphoid organs45.

Conversely CNS disease is also capable of inflicting immune dysfunction and a classic example in this case is ischaemic stroke. Here, the disruption of cerebral blood flow results in an initial infarct48 that subsequently induces debilitating systemic immunosuppression, predisposing patients to infections49–55. In experimental stroke models, studies have implicated SNS over-activation as a key mediator in increasing the susceptibility to bacterial aspiration pneumonia by modulating adaptive immunity by decreasing the frequency and functional responsiveness in B52 and T cells50,56,57. Other have shown that even the innate arm is not spared as there is loss of in the numbers and functional capacity of  NK cells to secrete cytokines55 as well the oxidative burst of monocytes and neutrophils58. However, these findings have not translated into clinical benefits as neither prophylactic antibiotics nor sympathetic blockade appear to confer any protection from increased susceptibility to bacterial aspiration pneumonia59–61.

Similarly, even neurodegenerative conditions such as Alzheimer’s disease (AD) have been shown to possess an immune component62 and therefore, it comes as no surprise that increased susceptibility to sporadic late-onset AD is linked to polymorphisms in genes of the immune system such as TREM2 and CD3363–65. It is thought that the deposition of amyloid-b (Ab)62,66 and the development of neurofibrillary tangles of hyperphosphorylated tau67 are key to disease pathogenesis. However, it is only recently that we have attempted to discern the differential contributions of various immune cell populations to the progression of AD16. It has now emerged that not all aspects of neuroinflammation are detrimental and that existence of T cells are key to restraining AD pathology68 and their rejuvenation through checkpoint inhibitors is vital to restoring type II interferon signalling69 that is dampened in aging70. However, it remains to be seen if these immune modulatory therapies can be translated from the bench to bedside.

Where next?

Whilst our appreciation of the multi-faceted interactions between the CNS and the immune system has grown, it is far from complete as we have been forced to revisit the notion of immune privilege the CNS was thought to enjoy. We have also refined our understanding of the CNS-resident microglia, specifically, their ontogeny and relationship with monocytes and macrophages in the mononuclear phagocyte system47,71–74. But more questions remain. What is the rationale to compartmentalise CNS immunity between cells in the parenchyma and those at the border? Do CNS niches endowed with the capacity to mediate protective effects exist? What is the T cell receptor repertoire exercised by T cells in the CNS23? The pursuit of answers to these questions could perhaps facilitate better understanding of the neuro-immune crosstalk and guide targeted approaches to therapeutic interventions to diseases of the CNS or immune system.


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