Editorial on the Research Topic
Neuroimmune Interface in Health and Diseases
Neuroimmunology is a field that investigates the bi-directional communication between
the nervous system (CNS and PNS) and the immune system. While these two physiological
systems were traditionally thought to act independently and that the brain was a privileged
site protected by the blood–brain barrier (BBB), researchers now appreciate the highly
organized cross talk between the immune and nervous systems in health and disease.
This conceptual shift came with a series of pioneering experiments by Hugo Besedovsky
who demonstrated that the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic
nervous systems were activated in response to a foreign antigen in rats (1). Injection
of sheep red blood cells in rats coincides with enhanced levels of circulating corticosterone
as well as decreased noradrenaline turn over in the hypothalami of rats. With Charles
Dinarello, who first cloned interleukin (IL)-1β, Besedovsky demonstrated that IL-1β
is responsible for the development of the brain response to peripheral immune stimulation
(2, 3). During the same year, Ed Blalock demonstrated that the production of adrenocorticotropic
hormone by leukocytes is induced by corticotropin-releasing hormone (3, 4). The CNS
communicates with the immune system via hormonal and neural pathways. The hormonal
pathway is predominantly via the HPA axis, which is the primary stress center in rodents,
primates, and humans. The neural pathway is mediated via the sympathetic and parasympathetic
(the vagus nerve) response. In turn, the immune system signals the CNS via cytokines
released by activated immune cells in the periphery but also through activated microglia
and astrocytes in the spinal cord and brain. The peripheral inflammation can lead
to central proinflammatory milieu and ultimately to sickness behavior defined as a
set of behavioral changes that develop in individuals during the course of systemic
inflammation (i.e., fever, lethargy, hyperalgesia). Cytokines released at the periphery
can reach the brain through the circumventricular organs, areas devoid of BBB such
as the organum vasculosum lamina terminalis, or through transport and secretion by
BBB cells (5).
The access of immune cells and other mediators to the CNS is controlled by the BBB.
However, in the event for instance of brain or spinal cord trauma, exposure to environmental
toxicants, and inflammation including infection and autoimmune diseases, etc. this
barrier can be breached. BBB dysfunction may be seen in a number of neurodegenerative
disorders (6) including amyotrophic lateral sclerosis (ALS). Patients with ALS were
shown to have enhanced neurovascular permeability (7). However, whether BBB breakdown
is the cause or consequence of ALS is still unknown and more studies are needed to
clarify the role of BBB breakage in the onset of ALS and of other neurodegenerative
disorders.
McKee and Lukens summarize in their review paper the current understanding of the
role of immune cells in traumatic brain injury pathogenesis (McKee and Lukens), while
Imamura and Hasegawa-Ishii discuss the immune response in the olfactory mucosa following
exposure to environmental toxicants (Imamura and Hasegawa-Ishii).
Pain, is the topic of four articles in this special issue. Zouikr and Karshikoff provide
an in-depth overview of the role of the cross talk between the endocrine, immune,
and central nervous systems in pain as well as the importance of taking early life
history into account when treating patients with chronic pain (Zouikr and Karshikoff).
Barr and colleagues demonstrate that nerve and root compression in postnatal (P) day
10, 14, 21, and 28 rats produced thermal hyperalgesia and mechanical allodynia that
was accompanied by enhanced proinflammatory cytokines and chemokines in the spinal
cord. The extent of hyperalgesia and immune activation was greater in older animals
(Barr et al.). Pain is a common symptom among patients with multiple sclerosis (MS),
using an animal model of MS-induced pain, namely, experimental autoimmune encephalomyelitis
(EAE), the team lead by Moalem-Taylor showed that even prior to the onset of clinical
EAE, mice already developed mechanical allodynia. This coincided with enhanced levels
of Iba1, a marker of microglia, in the spinal cord. Mice with EAE also exhibited increased
facial grimacing in the mouse grimace scale during clinical disease (Duffy et al.).
Hua in her review argues that opioid-containing immune cells play an important role
in peripheral analgesia in inflamed tissue.
Disruption of immune to brain communication is known to increase the susceptibility
of developing psychopathological and neurological disorders. In his review, Neupane
argues that dysfunctioning of the neuroimmune system could influence the development,
progression, and outcome of alcohol use disorder (AUD) and major depression (MD) comorbidity
and therefore neuroimmunological alteration should be taken as a key pathophysiological
factor when considering the comorbidity between AUD and MD. Karshikoff and Lasselin
review the current understanding on the relationship between inflammation and fatigue
and argue that the multidimensional aspect of fatigue should be considered when investigating
inflammation-induced fatigue (Karshikoff et al.). Edmonson et al. provide a very informative
review on the important role of microglia in maintaining a healthy neural network
and that abnormal microglial activity can lead to autism. Of particular importance,
abnormalities of microglia at the genetic and epigenetic level may contribute to the
pathogenesis of autism spectrum disorder. Over-reactivity of microglia has been identified
in patients with bipolar disorder, Ohgidani et al. developed a genius technique to
induce microglia-like from monocytes. They found a downregulation of CD206, a mannose
receptor expressed at the surface of macrophages, endothelial cells, and dendritic
cells, during the manic state among three patients with bipolar disorder. This is
an important translational study that provides the first evidence that the gene profiling
patterns are different between manic and depressive states (Ohgidani et al.). Maintaining
a healthy microglia–neuron interaction is critical for neuronal function homeostasis,
Wohleb provides an in-depth overview of the importance of neuron–microglia communication
in determining homeostatic neuronal function and that alteration in this bi-directional
communication can lead to mental health disorders. Microglia can constitute a reservoir
for the human immunodeficiency virus (HIV) that use these immune cells to silence
its transcription producing a state of viral latency. Marban et al. discuss the different
molecular mechanisms involved in the establishment and persistence of HIV latency
in brain reservoirs as well as the importance of understanding these molecular mechanisms
in order to purge or at least reduce the pool of latently infected brain cells.
The leptomeninges, choroid plexus, attachment of choroid plexus, perivascular space,
circumventricular organs, and astrocytic endfeet construct the histological architecture
that provides a location for intercellular interactions between bone marrow-derived
myeloid lineage cells and brain parenchymal cells under non-inflammatory state but
also during the early stages of systemic inflammation. Shimada and Hasegawa-Ishii
propose a mechanism connecting systemic inflammation, brain-immune interface cells,
and brain parenchymal cells and discuss the relevance of this immune to brain interaction
in the context of neurological disorders.
Amyotrophic lateral sclerosis is a debilitating neurodegenerative disorder characterized
by a progressive degeneration of motoneurons in the spinal cord and motor cortex.
Bone marrow transplantation (BMT) is a promising approach to recompensate the loss
of spinal motoneuron in ALS; however, adequate conditioning of BMT is a complex task.
In their research article, Peake and colleagues showed that conditioning mice with
higher dose of busulfan followed by BMT lead to higher accumulation of bone marrow-derived
cells in the spinal cord which was due in part to proliferation of these cells, as
well as enhanced microglial activity 7 weeks post-transplant. The authors also demonstrate
that in mSOD mice (a mouse model of ALS) conditioned with busulfan, a much higher
level of BMDCs accumulation in the spinal cord was observed compared to that of wild-type
mice (Peake et al.). However, whether these transplanted stem cells differentiate
into motoneurons and whether this is associated with functional recovery in ALS patients
is still not known.
As editors, we would like to express our gratitude to all of the scientists around
the globe who contributed to this special issue and we hope that you will enjoy reading
it.
Author Contributions
IZ, SH-I, and AS wrote the editorial and approved the final version.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.