Neuroimmunomodulation and Aging

Abstract

Inflammation is by definition a protective phase of the immune response. The very first goal of inflammation is destroying and phagocytosing infected or damaged cells to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, we now know that during many chronic neurological disorders, inflammation and degeneration always coexist at certain time points. For example, inflammation comes first in multiple sclerosis, but degeneration follows, while in Alzheimer’s or Parkinson’s disease degeneration starts and inflammation is secondary. Either way these are the two pathological detectable problems. The central nervous system (CNS) has long been viewed as exempt from the effects of the immune system. The brain has physical barriers for protection, and it is now clear that cells in the nervous system respond to inflammation and injury in unique ways. In recent years, researchers have presented evidence supporting the idea that in the CNS there is an ongoing protective inflammatory mechanism, which involves macrophage, monocytes, T cells, regulatory T-cells, effector T cells and many others; these, in turn, promote repair mechanisms in the brain not only during inflammatory, and degenerative disorders but also in healthy people. This “repair mechanism” can be considered as an intrinsic part of the physiological activities of the brain. It is now well known that the microenvironment of the brain is a crucial player in determining the relative contribution of the two different outcomes. Failure of molecular and cellular mechanisms sustaining the “brain-repair programme” might be, at least in part, a cause of neurological disorders. Today, the neurotoxic and neuroprotective roles of the innate immune reactions in aging, brain injury, ischemia, autoimmune and neurodegenerative disorders of the CNS are widely investigated and highly debated research topics. Nevertheless, several issues remain to be elucidated, notably the earlier cellular events that initiate dysregulation of brain inflammatory pathways. If these inflammatory processes could be identified and harnessed, then cognitive function may be protected during aging and age-related neurodegenerative diseases through early interventions directed against the negative consequences of inflammation. This commentary highlights the major issues/opinions presented by experts on the involvement of the brain immune system in aging and age-related diseases in a special edition of the journal Aging and Disease.

The growing number of older adults in the United States and other industrialized countries has prompted scientific interest in the health consequences of aging. Normal aging in humans brings a progressive loss in memory and is often exacerbated by diseases such as Alzheimer’s disease (AD). How does the single physiological process of aging lead to such diverse pathological states? Although many underlying processes have been invoked, one common ground that links many factors associated with cognitive aging is neuroinflammation. Markers of inflammation are associated directly with deficits in cognitive function and with diseases that are risk factors for cognitive decline [1–5]. Amelioration of brain inflammation with various treatments has beneficial actions on several indicators of impaired cognitive aging [6–8]. Understanding how neuroinflammation affects cognition may provide directions for useful interventions to prevent or treat an aberrant cognitive decline in older adults.

However, to better understand inflammation’s role in disease, it is necessary to be cognizant that inflammation is per se a protective response of our body that occurs in response to an insult. In the case of infection, the immune system is activated to identify the foreign agent and neutralize it. This involves a series of events and requires the recruitment of a variety of immune cells. Throughout most of the body, cells known as macrophages, search for invaders, and then engulf and neutralizing them. The recognition of infectious non-self is mediated by a limited number of germline-encoded pattern-recognition receptors (PRRs), which trigger rapid responses. In the brain, supporting cells of the glial family comprise of astrocytes and microglia. Microglial cells, act as scavengers, and are considered ‘the CNS professional macrophages’. Microglia are myeloid lineage cells expressing a wide range of PRRs and for this reason they embody the innate immune response of the brain, as they provide the first line of defense whenever there is an injury. They engulf and eliminate dead neurons that have been damaged by injury or illness. However, they also secrete harmful neurotoxins and toxic oxygen free radicals in an attempt to neutralize foreign or undesirable substances. Unfortunately, sometimes the injurious event overwhelms the protective effect, and inflammation may become self-perpetuating. Such is the case of normal aging, but likely much more rampant in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, which are characterized by exacerbated microglial activity. To date, the neurotoxic and neuroprotective roles of innate immune reactions in brain injury, ischemia, autoimmune and neurodegenerative disorders of the CNS, altogether solicits an intensively investigated and debated scientific research issue. However, despite considerable work in this area, much remains to be elucidated, notably cellular events regarding the early dysregulating events that activate brain inflammatory pathways. If we will be able to target and harness these inflammatory processes toward therapeutic application, then cognition could be protected during aging and disease by early intervention against the negative consequences of inflammation. In this special issue focused on Neuroimmunomodulation and Aging, multiple experts from the field give their views on the involvement of the brain immune system in aging and age-related disease.

This issue opens with an interesting original article by Chen et al [9] which examined the ability of human umbilical cord blood cells (HUCB) to enhance the proliferation, survival and neuritic outgrowth of hippocampal neurons harvested from the adult and the aged brain. The HUCB cells have been shown to possess the ability for both providing trophic support and reducing inflammation in aging and neurodegenerative diseases. In this article, using long-term in vitro assays, authors’ report that HUCB cells are able to protect as well as promote the dendritic growth of hippocampal neurons harvested from the young adult and the aged rat brain. Furthermore, authors report the ability of HUCB cells to induce proliferation of a population of hippocampal neurons derived from the adult and the aged brain. Additional assays imply that these protective effects are linked to the release of growth factors and cytokines produced by the HUCB cells. See the article by Chen et al for details [9].

The second original article by Paredes et al [10] investigates the role of TNFa in cerebellar dependent motor learning. In this study, young and aged rats were injected with recombinant TNFα and anti-rat TNFα respectively, prior to a classical eye blink conditioning coupled with microdialysis in the cerebellum, which facilitated the detection of the neurotransmitter release in response to eye blink conditioning. The results of this study demonstrated a critical correlation between TNFα, aging and modulation of norepinephrine (NE) release during the delayed eyeblink conditioning learning. Young rats given TNFα showed a decreased rate of learning and a decrease in NE release compared to control animals. On the other hand, aged animals in which TNFα action was blocked showed improved motor learning and an increased NE release compared to the control group. This study underscored that cerebellar physiology is somewhat vulnerable to the presence of high levels of TNFα during aging.

The issue continues with a critical review by Lynch and colleagues [11] on glial activation in the aged brain. The authors begin by presenting a comprehensive review of the astrocyte-neuron interactions in the young and aged brain, as well as in age-related neurodegenerative diseases. Lynch and co-workers also discuss astrocyte function in synaptic plasticity and in an inflammatory response. The authors present evidence that supports the hypothesis that the age-related astrogliosis and astrocytosis are responsible for the increase in pro-inflammatory cytokines. They move on to review the role of microglia in the healthy and the aged brain and in response to amyloid plaques in the brain of AD patients and mouse models of AD. They particularly highlight the recent research reporting evidence both in support and against the detrimental or beneficial role of microglia in normal aging and age-related neurodegenerative diseases.

Carrying on the theme of brain inflammation, Streit and colleagues focus on the characteristics of microglia in the aged brain and on the microglial dysfunction hypothesis, which advances the premise that microglia are entirely beneficial and supportive in terms of maintaining CNS homeostasis [12]. Over the past few years the Streit research team has developed this interesting theory of “microglial senescence”, noting that microglia become dysfunctional with age and are not able to respond to appropriate stimuli. This unresponsiveness of the microglia leads to both increased susceptibility to brain infection, as well as increased susceptibility to neurodegeneration and are subject to loss of mitotic ability after several rounds of replication. The authors also present evidence of abnormal microglia (dystrophic microglia) in the aged human brain, whose morphology differs from that observed in the aged rodent microglia. The observation that the incidence of dystrophic microglia increase in older individuals supports the hypothesis that dystrophy is a reflection of the aging cell.

Several lines of evidence suggest a correlation between adult neurogenesis and learning. The review by Gemma and colleagues [13] explores the involvement of brain inflammation in age-related decrease in hippocampal neurogenesis and memory function. They discuss the recent finding that there is a robust bidirectional communication between microglia and neurons. They particularly discuss studies that demonstrate that dysfunction of the neuron/microglial signaling leads to a state that primes inflammation- and microglia-mediated neurotoxicity. The authors also review the function of two important neuroimmune-modulators molecules, fractalkine and CD200 that are responsible for such communication, showing that an interruption in neuron/microglial signaling impairs hippocampal neurogenesis and memory function.

Barrientos et al [14] continue on with the theme of the influence of inflammation on synaptic plasticity during aging, but focus rather on the impact of peripheral immune challenges on the hippocampal function. The authors first presented evidence that aged animals following a challenge with bacteria, virus or surgical intervention, exhibit an exaggerated inflammatory response in the brain. The authors showed that aged animals peripherally treated with LPS when exposed to a spatial and contextual memory task (Morris water maze and Fear conditioning) display deficit in long term memory compared to corresponding LPS-treated young animals. The authors proceed to identify the immune-to-brain signaling responsible for the hippocampal dysfunction following peripheral infection. The authors describe IL-1b and the consequent activation of MAP kinases JNK and p38, as one of the main players of this inflammatory cascade.

As briefly described by the preceding authors, p38 MAP kinase is a key signal transduction factor involved in the production of IL-1β and TNFα. Bachstetter and Van Eldik explore in detail the role of p38 MAP kinase and related isoforms, in regulating cytokine production [15]. They extend this discussion to presenting small molecule inhibitors of the p38 MAP kinase family that have been developed as therapeutic candidates, which show efficacy in blocking the production of IL-1b and TNFa.

Next, Reese and Taglialatela [16] review the role of phosphatase calcineurin in physiological aging and AD. The authors first discuss the involvement of calcineurin in many neuronal (or non-neuronal) physiological functions. Later they review evidence in support of the hypothesis that calcineurin acts as a bi-directional enzyme for neuronal cell survival and death (i.e. having protective and toxic actions), and the balance of the bi-directional effects may be important in aging. Finally the authors discuss how calcineurin hyperactivity could cause deficit in cognitive function and neuroinflammation in AD.

Taken together, the articles in this issue summarize the current knowledge concerning the state of inflammation in the aged brain. While inflammation is traditionally considered as a purely detrimental event in aging and age-related neurodegenerative diseases, authors highlight studies that support inflammation as a therapeutic event, which could be modulated to abrogate the devastating cognitive deficits associated with AD and other disorders with altered inflammatory response.