Multiple sclerosis (MS): MS is a neurodegenerative disease affecting around 2.5 million
people worldwide, representing the second cause of disabilities in the young adult
population. MS is a demyelinating pathology which originates in the autoimmune attack
of T and B lymphocytes against myelin. This lack of myelin leads, in turn, to axonal
degeneration, neuronal death and the consequent neurological disabilities (Franklin
and Ffrench-Constant, 2017). A main hallmark of MS is a preserved local neuroinflammatory
environment. It is now acknowledged that this persistent inflammatory scenario is
a central and common condition in almost all neurodegenerative pathologies (as in
Parkinson’s and Alzheimer’s diseases, among others) controlling and modulating the
regulatory responses of the system to the triggering insult. In the case of MS, this
original insult corresponds to the loss of myelin (Chitnis and Weiner, 2017; Franklin
and Ffrench-Constant, 2017). Of particular interest for the understanding of MS progression,
is how and when surrounded pro- and anti-inflammatory cytokines and chemokines modulate
cross-glial communication in demyelinated lesions. After a demyelinated insult there
is an -unfortunately deficient or incomplete- spontaneous myelin repair process (i.e.,
remyelination), characterized by the highly interdependent function of microglia,
astrocytes and oligodendroglia, the latest corresponding to cells responsible for
the formation of myelin in the central nervous system (CNS) (Chitnis and Weiner, 2017;
Franklin and Ffrench-Constant, 2017). For instance, it is known that signaling molecules
released by microglia induce the activation of astrocytes and promote differentiation
of oligodendrocytes in demyelinated areas (Franklin and Ffrench-Constant, 2017). Similarly,
astrocyte activity and secretion can promote oligodendrocyte maturation (Franklin
and Ffrench-Constant, 2017). In the complex cellular interaction observed in demyelinated
lesions, connexin (Cx)-based channels and hemichannels has been pointed out as a major
components underlying glial communication (Vejar et al., 2018). However, less attention
has been paid to the putative role of pannexin (Panx)-based channels, a functional
equivalent of Cxs, usually involved in inflammatory processes, particularly in the
CNS. Here we discuss evidence supporting a role of pannexin-based channels on the
progression of MS that, we believe, deserves further investigation.
Role of Panx 1 in glial cells: Panxs are a family protein conformed by three members:
Panx1, Panx2 and Panx3. These proteins form a channel, or pannexon, in the plasmatic
membrane which is permeable to ions and other molecules such as ATP (Avendaño et al.,
2015; Ahmadian et al., 2019). They are found in several cell types participating in
diverse physio- and pathological events, such as cellular proliferation, differentiation,
migration, inflammatory responses, cytokines release, muscle contraction, glucose
uptake and modulation of the nervous system (Ahmadian et al., 2019). Different open
conformation of Panx1-based channels has been proposed, displaying different permeabilities
where ATP release (widely validated) is associated with a large conductance conformation
(~500 pS) (Suadicani et al., 2012).
In the CNS Panx1 channels are expressed in neurons, glial (astrocytes, microglia and
oligodendrocytes) and endothelial cells (Ahmadian et al., 2019). In neurons, it has
been shown that reactive oxygen and nitrogen species (especially NO) increases the
activity of Panx1-based channels during oxygen/glucose deprivation in a hippocampal
ischemia/reperfusion model, suggesting a close relationship between oxidative stress
and Panx1 (Ahmadian et al., 2019).
Regarding glial cells, Panx1 have been pointed out as a potential factor in astrocyte
survival under physio- and pathological conditions (Suadicani et al., 2012; Freitas-Andrade
and Nauss, 2016). Indeed, some authors hypothesize that Panx1 serve as K+ sensors
in astrocytes, playing a central role in K+ homeostasis, the major documented astrocyte
function in the CNS (Suadicani et al., 2012). In cultured spinal astrocytes the activation
of purinergic ionotropic 2X receptors (P2XRs) by ATP trigger the opening of Panx1-based
channels, leading to ATP-induced ATP release and the resulting Ca2+ entry. Although
this mechanism is not unique (for instance, Cx43 hemichannels can be also opened)
(Freitas-Andrade and Nauss, 2016), Panx1-based channel has a key role maintaining
the ATP signaling, since in cultured astrocytes from a Panx1-null mouse, the ATP-dependent
calcium wave propagation is impaired (Suadicani et al., 2012).
Several studies link Panx1-based channels activity with neurodegenerative disorders
and/or inflammation conditions (Avendaño et al., 2015; Freitas-Andrade and Nauss,
2016; Ahmadian et al., 2019). For example, a prenatal inflammatory condition (triggered
by lipopolysaccharide exposure during pregnancy) increases the release of ATP from
astrocytes in the offspring by opening Panx1 channels (along with Cx43 hemichannels)
(Avendaño et al., 2015). In the same study authors reported that Panx1 and Cx43 surface
levels were up-regulated, resulting in an increase of neuronal death mediated by the
activation of neuronal Panx1-based channels and P2X7 receptors (Avendaño et al., 2015).
This increase of astrocytic Panx1 channels activity was induced by an increment in
the levels of tumor necrosis factor-α and interleukin-1β (IL-1β), that in turn increased
ATP release through Panx1 (and Cx43)-based (hemi)channels in astrocytes of the offspring
(Avendaño et al., 2015). Also, under inflammatory conditions nod-like-receptor pyrin
domain-containing 3 inflammasome activation is inhibited by probenecid, a Panx1 channel
blocker (Ahmadian et al., 2019). Since nod-like-receptor pyrin domain-containing 3
plays a key role in the pathogenesis of Parkinson’s disease it is likely that Panx1-based
channels activity contributes importantly to the inflammatory cascade underlying this
neurodegenerative disease (Ahmadian et al., 2019). In this line, the administration
of probenecid reduces inflammation, cerebral edema and neuronal death, in mice subjected
to transient focal ischemia, reinforcing (i) an ubiquitous role for Panx1 in neuroinflammatory/detrimental
conditions and (ii) the notion that an increase of Panx1-based channels activity might
be a harmful signal, since neuroprotection is observed when a Panx1 channel blocker
is applied (from Freitas-Andrade & Nauss, 2016)
Pannexin 1 as a novel regulator of MS: Given the well supported role of Panx1-based
channels in inflammation and important neurodegenerative disorders, a putative function
of these channels in MS progression–characterized precisely by a neuroinflammatory
context– is expected. Indeed, recent findings showed that probenecid reduced clinical
symptoms (disease score) in the experimental autoimmune encephalomyelitis MS model,
reducing inflammation, the number of T lymphocytes infiltrating the spinal cord, and
the loss of oligodendroglia lineage cells (Hainz et al., 2016, 2017b). Importantly,
the same authors also showed that probenecid improved remyelination of the optic nerve
in a cuprizone-induced demyelinated model of MS (Hainz et al., 2017a). Even though
the subcellular mechanisms are still missing, these studies suggest a specific improved
outcome after probenecid treatment, namely: myelin regeneration.
An interesting observation is that Panx1 levels are upregulated by IL-1β in peripheral
tissue (bladder mucose) of experimental autoimmune encephalomyelitis mice (Negoro
et al., 2013), as was also report in a systemic inflammatory condition (triggered
by lipopolysaccharide) (Avendaño et al., 2015), confirming that cytokines can modify
Panx1 levels in a relevant clinical model of MS (Negoro et al., 2013), thus these
authors suggest that Panx1 signaling provides positive feedback in a dysfunction associated
with MS (Negoro et al., 2013). Supporting a putative role for Panx1-based channels
in MS, IL-1β is one of the main cytokines released by the activated microglia recruited
in demyelinated regions, being thus likely that this signaling molecule regulates
Panx1 level in MS lesions.
But how could Panx1-based channels activity regulates (re)myelination? A first direct
possibility might be by modulating the extracellular ATP levels. It has been reported
that myelin synthesis depends, at least partially, on ATP signaling (Wake et al.,
2011). Thus, under physiological conditions, since ATP is released by high conductance
Panx1-based channels, their activity could greatly modify the local amounts of available
ATP that in turn could signaling to oligodendroglia controlling its potential to synthesize
new myelin (Wake et al., 2011). However, in an inflammatory scenario, an increase
of Panx1 levels and/or Panx1-channel activity could lead to cell damage by a toxic
entry of calcium through a P2XRs overactivation in oligodendroglia (
Figure 1
). Alternatively, indirect modifications of another cellular partners such as astrocytes,
can modify the potential for myelin regeneration. Indeed, blocking Panx1 expression
in astrocytes by siRNA transfection, inhibited cytokine (interleukin-6 and -8) and
glutamate release (Wei et al, 2015), both molecules pointed out as key factors in
the process of myelination and remyelination, raising thus another possible mechanism
for Panx1 involvement on MS: the modulation of molecules and cells commonly present
in demyelinated lesions.
Figure 1
Summary of the proposed mechanism.
After a demyelinated insult, recruited microglia and astrocytes release several inflammatory
molecules such as IL-1β, IL-23, IFN-γ, TNF-α, among others, that can regulate the
potential for remyelination by modifying oligodendroglia proliferation and maturation.
Under multiple sclerosis neuroinflammatory conditions, an increase in the IL-1β levels
might increase the activity and levels of Panx-1 based channels which in turn might
induce a toxic level of intracellular calcium and impaired ATP signaling in the glial
cell population leading to an impaired remyelination. IFN-γ: Interferon-γ; IL: interleukin;
TNF-α: tumor necrosis factor-α.
Concluding remarks: Currently there are no effective treatments for MS, therefore
the study of relevant factors underlying the pathophysiological progression of the
disease is a challenge for translational research. As other neurodegenerative disorders,
MS is characterized by a chronic neuroinflammatory environment as well as the release
of chemo- and cytokines as well as reactive oxygen and nitrogen species. Since (i)
Panx1 is a common molecule interacting with these factors during the progression of
neuroinflammation in many different scenarios, (ii) Panx1 levels and activity is modified
in response to molecules commonly present in demyelinated lesions, (iii) Panx1 is
expressed in glial cells participating in the myelin repair process, (iv) ATP, a molecule
implicated in myelin synthesis, can be released by Panx1-based channels and (v) recent
studies have shown that blocking Panx1 channels improve the symptomatology and promote
myelin repair in MS animal models; we here proposed that Panx1 might play a central
role on the progression of MS, and therefore deserves further investigation. To determine
Panx1 involved pathways at cellular and subcellular levels becomes especially important
when a clinically approved drug targeting Panx1-based channels (i.e., probenecid)
is available. Next research lines might consider the putative mechamisms proposed
herein (
Figure 1
)in order to shed light on novel mechanisms underlying MS progression and myelin repair.
This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT),
No. 11160536 (to CP) and 11160616 (to FCO).
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