Mast Cells, Glia and Neuroinflammation Partners in Crime

doi:10.1111/imm.
12170 REVIEW SERIES ON IMMUNE RESPONSES IN NEURODEGENERATIVE DISEASES

IMMUNOLOGY Series originated from a session at BSI Congress 2013
Mast cells, glia and neuroinflammation: partners in crime?
OTHER ARTICLES PUBLISHED IN THIS SERIES

Innate and adaptive immune responses in neurodegeneration and repair. Immunology 2014; 141:287291.
The impact of neuroimmune changes on development of amyloid pathology; relevance to Alzheimers disease. Immunology 2014; 141:292301.
Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 2014; 141:302313.
Can we switch microglias phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology 2014; 141:328339.
T cells in the central nervous system: messengers of destruction or purveyors of protection? Immunology 2014; 141:340344.
Stephen D. Skaper, Laura Facci and Summary

Pietro Giusti
Glia and microglia in particular elaborate pro-inflammatory molecules
Dipartimento di Scienze del Farmaco, Largo
that play key roles in central nervous system (CNS) disorders from neuro-
Egidio Meneghetti 2, Universita degli Studi
di Padova, Padova, Italy pathic pain and epilepsy to neurodegenerative diseases. Microglia respond
also to pro-inflammatory signals released from other non-neuronal cells,
mainly those of immune origin such as mast cells. The latter are found in
most tissues, are CNS resident, and traverse the bloodspinal cord and
bloodbrain barriers when barrier compromise results from CNS pathol-
ogy. Growing evidence of mast cellglia communication opens new per-
spectives for the development of therapies targeting neuroinflammation
by differentially modulating activation of non-neuronal cells that normally
control neuronal sensitization both peripherally and centrally. Mast
cells and glia possess endogenous homeostatic mechanisms/molecules that
can be up-regulated as a result of tissue damage or stimulation of inflam-
matory responses. Such molecules include the N-acylethanolamine family.
One such member, N-palmitoylethanolamine is proposed to have a key
role in maintenance of cellular homeostasis in the face of external stres-
sors provoking, for example, inflammation. N-Palmitoylethanolamine has
proven efficacious in mast-cell-mediated experimental models of acute
and neurogenic inflammation. This review will provide an overview of
recent progress relating to the pathobiology of neuroinflammation, the
role of microglia, neuroimmune interactions involving mast cells and the
possibility that mast cellmicroglia cross-talk contributes to the exacerba-
tion of acute symptoms of chronic neurodegenerative disease and acceler-
Received 10 July 2013; revised 31 August
2013; accepted 04 September 2013.
ates disease progression, as well as promoting pain transmission
Correspondence: Stephen D. Skaper, Dipar- pathways. We will conclude by considering the therapeutic potential of
timento di Scienze del Farmaco, Universita treating systemic inflammation or blockade of signalling pathways from
degli Studi di Padova, Largo E. Meneghetti the periphery to the brain in such settings.
2, Padova 35131, Italy.
E-mail: [email protected] Keywords: mast cells; microglia; neurodegeneration; neuroinflammation;
Senior author: Stephen D. Skaper neuroprotection; palmitoylethanolamide.
Abbreviations: ALS, amyotrophic lateral sclerosis; CNS, central nervous system; FAAH, fatty acid amide hydrolase; IL-1b, inter-
leukin-1b; MPL, monophosphoryl lipid A; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NAAA, lysosomal NAE-hydroly-
sing acid amidase; NAE, N-acylethanolamine; NAPE, N-acylated phosphatidylethanolamine; PAMP, pathogen-associated
molecular patterns; PEA, palmitoylethanolamide; PPAR, peroxisome proliferator activated receptor a; TLR, Toll-like receptor;
TNF-a, tumour necrosis factor-a
314 2013 John Wiley & Sons Ltd, Immunology, 141, 314327
REVIEW SERIES ON IMMUNE RESPONSES IN NEURODEGENERATIVE DISEASES
Mast cells, glia and neuroinflammation
metabolism and behaviour including the expression of

Introduction
a pro-inflammatory phenotype by microglia.18 It has been
Inflammation is fundamentally a protective cellular proposed that in multiple chronic disease states, and in
response aimed at removing injurious stimuli and initiat- ageing, microglia are primed by previous pathology, or by
ing the healing process. However, when prolonged, genetic predisposition, to respond more vigorously to
inflammation overrides the bounds of physiological con- subsequent inflammatory stimulation, so transforming an
trol and eventually becomes destructive. Inflammation adaptive CNS inflammatory response to systemic inflam-
increasingly surfaces as a key element in the pathobiology mation, into one with deleterious consequences.19 It
of chronic pain, neurodegenerative diseases, stroke, spinal therefore goes without saying that delineating the signal-
cord injury and perhaps even neuropsychiatric disor- ling pathways underlying glial cell activation is crucial in
ders.15 A plethora of pro-inflammatory cytokines, eicosa- the design of agents capable of antagonizing such signal-
noids and other immune neurotoxins, have been found ling steps which may translate into therapeutic benefit
in cerebrospinal fluid and/or affected brain regions of for neurodegenerative disorders and neuropathic pain.
patients with neurodegenerative disorders.6 Consider also Although it is widely accepted that glial cell activation
that nuclear factor-jB, a requisite transcription factor for contributes to neuropathology, one must not forget that
most pro-inflammatory molecules, is activated in the microglia and astrocytes also respond to pro-inflamma-
substantia nigra pars compacta of Parkinsons disease tory signals released from other cells of immune origin.
patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine In this view, mast cells represent a potentially important
(MPTP) -intoxicated mice and monkeys, and its selective (and underappreciated) peripheral immune signalling link
inhibition protects dopaminergic neurons from MPTP to the brain in an inflammatory setting (Fig. 1). Mast
toxicity.7 It is intriguing to note that neuroinflammation cells share similarities with basophil granulocytes in
may also raise the brains sensitivity to stress.8 Indeed, a blood, although the former are likely generated by differ-
recently published study by Zhang et al.9 reports that ent precursor cells in the bone marrow.20 In contrast to
inflammation-activated signalling pathways in the brains basophils, mast cells circulate in an immature form until
hypothalamus control the production of ageing-related choosing a tissue site to settle which probably determines
hormones. This finding provides a link between inflam- their precise characteristics. These effector cells of the
mation, stress responses and ageing. Inflammation there- innate immune system are present in most tissues in the
fore constitutes an important target for neuronal vicinity of blood vessels, particularly near surfaces exposed
protection in neurodegenerative disorders and neuropath- to the environment.21 Mast cells participate in innate host
ic pain, the latter resulting from damage or disease affect- defence reactions, occur in peripheral tissues innervated by
ing the somatosensory system.10 small calibre sensory nerve fibres and within the endoneur-
Recognition that there is extensive communication ial compartment of peripheral nerves, and in meninges and
between the immune system and the central nervous sys- cerebral blood vessels. During development they enter the
tem (CNS) is, no doubt, one of the more fundamental brain by way of penetrating blood vessels, with which they
advances in neuroscience in recent times. Inflammatory remain associated.22 Mast cells can move through the
cytokines occupy a key niche in this network, regulating bloodbrain barrier of normal brain,23 but may also tra-
host responses to infection, inflammation, stress and verse the bloodspinal cord barrier and bloodbrain barrier
trauma. Glial cell activation has been implicated in the when compromised by disease. Interestingly, they are capa-
pathogenesis of Alzheimers disease, Parkinsons disease, ble of phagocytosis and antigen presentation, and can mod-
cerebral ischaemia, multiple sclerosis2,7,11 and motor neu- ulate the adaptive immune response (Box 1).
ron disease,12 and possibly schizophrenia and depres- Mast cells produce a vast array of mediators, which
sion.4,13 Microglia-mediated neuroinflammatory processes include biogenic amines, cytokines, enzymes, lipid metab-
are also proposed to compromise healthy brain aging.14 olites, ATP, neuropeptides, growth factors and nitric
Found to accumulate at sites of injury or plaques in neu- oxide (Table 1).24 Because of their heterogeneity, how-
rodegenerative CNS diseases,11,15 microglia scavenge dead ever, no single mast cell makes all of these. By nature of
cells and secrete neuron survival factors; the latter may their immune regulatory role they participate in IgE
have beneficial effects in the recovery of injured CNS. switching by B cells,25 and the release of chemoattractants
However, inappropriate and prolonged activation of glia that recruit eosinophils26 and monocytes.27 Certain dis-
can cause autoimmune responses leading to brain injury ease states, like those involving autoimmune demyelina-
and neuronal cell death.2,11,15 Glia provide a link also tion are accompanied by an increased absolute number of
between neuroinflammation and neuropathic pain;16 mast cells within the CNS, as well as those undergoing
microglia, in particular, show increased activity in multi- degranulation.28 Mast cell trypase is elevated in the cere-
ple pain-processing pathways in response to peripheral brospinal fluid of patients with multiple sclerosis.29 At
injury.17 Systemic inflammation gives rise to signals that the other end of the equation, activated mast cells can
communicate with the brain and leads to changes in provoke demyelination30 and induce apoptotic oligoden-
2013 John Wiley & Sons Ltd, Immunology, 141, 314327 315
S. D. Skaper et al.
Table 1. Mast cell mediators immune system.34 Release of interleukin-1b (IL-1b) from
Biogenic amines
spinal microglia as a consequence of inflammation/injury
Biogenic amines [histamine (25 pg/cell), serotonin] may, by engaging its receptor, induce phosphorylation of
Cytokines the N-methyl-D-aspartate receptor NR1 subunit to
Interleukins 16 strengthen painful signal transmission.35 Under pathologi-
Leukaemia inhibitory factor cal conditions dorsal horn microglia become activated
Tumour necrosis factor-a and show up-regulated expression of purinergic recep-
Interferon-c tors,36,37 whose inhibition or deletion strongly attenuates
Transforming growth factor-b neuropathic pain.3638
Granulocytemacrophage colony-stimulating factor Upon degranulation, mast cells release algogenic (from
Enzymes
the Greek algos for pain) substances which activate or
Acid hydrolases
sensitize nociceptors, thereby contributing directly to neu-
Chymase
Phospholipases
ropathic pain.39 Nerve-resident peripheral nerve mast cells
Rat mast-cell protease I and II represent the first line of activation at the point of damage
Trypase and facilitate recruitment of neutrophils and macrophag-
Lipid metabolites es.40 Mast cell degranulation activates trigemino-cervical
Prostaglandin D2 and lumbosacral pain pathways and elicits widespread tac-
Leukotriene C4 tile pain hypersensitivity,41 possibly mediated by a sensi-
Platelet-activating factor tizing effect of histamine on nociceptors. Rapid release of
Other bioactive molecules nerve growth factor from mast cells also produces sensiti-
Neuropeptides (e.g. vasoactive intestinal peptide, substance P) zation of nociceptors via the latters high-affinity nerve
Proteoglycans, mainly heparin (active as an anticoagulant)
growth factor-trkA receptors (and indirectly via other
Nerve growth factor
peripheral cell types).42 Interestingly, mast cells themselves
ATP
Nitric oxide
respond to nerve growth factor, in a paracrine/autocrine
fashion.43 These events promote the recruitment of T cells,
which reinforce and maintain inflammatory reactions. The
drocyte cell death.31 Brain mast cells might even bridge released mediators/factors can induce activity in axons
the immune system and anxiety-like behaviour.32 Theoha- and/or undergo retrograde transport to the cell body of
rides et al.33 have suggested that perinatal mast cell acti- dorsal root ganglion neurons, thereby affecting gene
vation by infectious, stress-related, environmental or expression. Further, mast cells may enhance recruitment
allergic triggers can lead to release of pro-inflammatory of other key immune cell types which, in turn, release
and neurotoxic molecules, so contributing to brain pro-nociceptive mediators, such as IL-6.44 Systemic gluco-
inflammation and autism-spectrum disorders pathogene- corticoid therapy reduces pain and the number of tumour
sis, at least in a subgroup of these patients. necrosis factor-a (TNF-a) -positive mast cells in rats with
chronic constrictive injury, strengthening a role for mast
cells in chronic pain states.45 Mast cells are also important
Microglia, mast cells and nervous system
mediators of chronic visceral pain.46
disease
Neuropathic pain Ischaemia and traumatic brain injury

Persistent pain represents a substantial and growing unmet Stroke and traumatic brain injury are characterized by an
medical need, affecting nearly half of people seeking inflammatory response in which microglia activation
medical care in the USA alone. Among all types of and macrophage/neutrophil infiltration are important
chronic pain, neuropathic pain stands out: this is pain elements.47 Left unchecked, this can ultimately lead to sec-
resulting from damage, degeneration or dysfunction of ondary injury. Yet, in certain instances attenuation of mi-
the sensory nervous system, and remains largely untreat- croglial activation can be beneficial.48 Considerable efforts
able. Central neuropathic pain is found in spinal cord have been directed also to inhibiting the consequences of
injury, multiple sclerosis and some strokes, whereas the blood-borne neutrophil and phagocyte infiltration in
common causes of painful peripheral neuropathies are ischaemia. In contrast, less emphasis has been placed on
diabetes and other metabolic conditions. Neuropathic brain-resident cell types able to mount an immediate host
pain is common in cancer as a direct result of cancer on response in the cerebral parenchyma and meninges, for
peripheral nerves or as a side effect of chemotherapy. The example, mast cells.49 Analogous to peripheral nerve dam-
triggering and maintenance of neuropathic pain states is age and contrary to what was long believed50 mast
strongly dependent on Schwann cells, spinal microglia cell activation is the first responder in this injury.51
and astrocytes, together with elements of the peripheral Although CNS microglia/macrophages and endothelial
cells produce TNF-a in response to stimuli, mast cells are neuron disease, affecting around 46 per 100 000. ALS is
primed to initiate acute inflammation with their stores characterized by a progressive dysfunction and degenera-
of pre-formed TNF-a.52 Treatment with mast cell-stabiliz- tion of both upper motor neurons comprising the corti-
ing agents limits the brain damage caused by perinatal cospinal tract, and lower motor neurons arising from the
hypoxiaischaemia and transient focal ischaemia.51,53,54 brainstem nuclei and ventral roots of the spinal cord.
Given their complement of vasoactive and matrix-degrad- Neuroinflammation is now established as an important
ing components like histamine, and proteases able to acti- aspect of pathology in ALS.64 There is a marked activa-
vate matrix metalloproteinases, mast cells are an early tion or proliferation of both microglia and astrocytes at
response element in the regulation of acute bloodbrain specific disease stages in mouse models of ALS65 and in
barrier changes after cerebral ischaemia and haemor- humans in vivo.66 There is also compelling evidence indi-
rhage.55 By regulating acute microvascular gelatinase acti- cating impairment of all neurovascular unit components
vation, cerebral mast cells can effect bloodbrain barrier including the bloodbrain and bloodspinal cord barriers
disruption following transient cerebral ischaemia.56 in both patients and animal models of ALS.67
As discussed earlier, mast cells participate in innate
host defence reactions, and orchestrate neuroinflammato-
Chronic neurodegenerative diseases
ry processes. Meningeal mast cells contain preformed
Microglia are activated in response to a number of different TNF-a (the only cell type to do so) and vasoactive media-
pathological states within the CNS including neurodegen- tors, which are able to regulate bloodbrain barrier56 and
erative disorders such as Alzheimers disease, Parkinsons bloodspinal cord barrier68 function and facilitate the
disease, multiple sclerosis, amyotrophic lateral sclerosis entry of lymphocytes, neutrophils and mast cells them-
(ALS), and AIDS dementia complex. There is a vast litera- selves69 when the barrier is compromised as a result of
ture on this facet of neuroinflammation that is beyond the CNS pathology, e.g. in ischaemic stroke and ALS, respec-
scope of this article. The reader is referred to several excel- tively. Indeed, degranulating70 and IL-17-expressing mast
lent recent reviews.57,58 In the case of Parkinsons disease, cells68 have been observed in the spinal cord of ALS
the oxidative stress response by microglial cells, most nota- patients, and serum levels of this cytokine are reported to
bly the activity of the enzyme NADPH oxidase, appears to correlate with the duration and severity of the disease.68
play a central role in the ensuing pathology.59 An interaction between mast cells and T regulatory
The case for mast cells, while somewhat analogous, lymphocytes can lead to increased IL-6 production by the
depends to a greater extent on the specific disease. In former,71 in turn promoting the activity of T helper type
patients with multiple sclerosis, especially in chronic 17 lymphocytes.72 Moreover, IL-15 and IL-12 are elevated
active plaques, mast cells have been noted generally clus- in the serum and cerebrospinal fluid of patients with
tered around venules and capillaries.60 Mast cell-associ- ALS.73 Interleukin-15 is a mast cell chemoattractant74
ated gene transcripts (e.g. tryptase) are also present in (potentially contributing to mast cell recruitment in
multiple sclerosis plaques, whereas mast cell mediators inflammatory responses), while mast cells are an impor-
such as tryptase and histamine have been found in cere- tant source of IL-12.75 Pathogen-associated molecular
brospinal fluid of multiple sclerosis patients, with levels patterns (PAMPs) are molecules associated with groups
rising during relapses.29,61 In mouse experimental autoim- of pathogens that are recognized by cells of the innate
mune encephalomyelitis models of multiple sclerosis, immune system. One important class of PAMP receptors
however, there is no clear evidence whether the mast cell is the transmembrane Toll-like receptors (TLRs). Interleu-
effects on experimental autoimmune encephalomyelitis kin-12 up-regulates expression of mast cell TLR2/TLR476
development depend on mouse strain, immunization pro- and proteinase-activated receptor-2,77 emerging targets
tocol or type and severity of disease.62 A role for mast for neuroinflammation.78
cells in Alzheimers disease pathogenesis remains to be Functional TLR2 and TLR4 expressed by mast cells and
established, although one report claimed that fibrillar microglia respond to molecules called damage-associated
amyloid b-peptides trigger CD47-dependent mast cell molecular patterns, one being the high mobility group
secretory and phagocytic responses.63 For Parkinsons dis- Box 1 protein found elevated in the spinal cord of ALS
ease, there is no clear evidence to support a relationship patients.79 Likewise, microglia-released IL-6 and CCL5
between brain mast cells and Parkinsons disease. As this could, conceivably affect surface TLR2 and TLR4 expres-
concerns mast cells and motor neuron disease, this point sion on mast cells,80 resulting in the up-regulation of
will be discussed separately below. numerous chemokines to induce a pro-inflammatory pro-
file in microglia.81 Given that ALS patients frequently
experience neuropathic pain, and that a transgenic mouse
Mast cells and ALS: at the crossroads?
ALS model develops peripheral nerve inflammation,82 one
Amyotrophic lateral sclerosis, also known as Charcots or might ask whether or not mast cells play a role here, as
Lou Gehrigs disease, is the most prevalent type of motor well.
S. D. Skaper et al.
Box 1. Mast cell ID chart
Origin and classification
1 First described by Paul Ehrlich in 1878 on the basis of their

G
unique staining characteristics and large cytoplasmic granules
2 Very close to basophil granulocytes in blood; current evidence
suggests that mast cells are generated by different precursor
cells in the bone marrow
3 Thought to originate from bone marrow precursors expressing
CD34; a distinct subset of mast cells can also be induced upon
host responses to inflammation
4 The haematopoietic lineage development of tissue mast cells is
unique compared with other myeloid-derived cells because it
is early lineage progenitors, undetectable by histochemistry,
that leave the bone marrow to enter the circulation. These
immature lineage mast cells immediately undergo transendo-
thelial recruitment into peripheral tissues wherein the appear-
ance of secretory granules with a particular protease Figure 1. Electron microscopic image of an isolated tissue mast cell.
phenotype is regulated by the peripheral tissue. Note the prominent appearance of numerous cytoplasmic granules.
5 Classified by their species-dependent protease constitution
rather than location
6 Present in most tissues in the vicinity of blood vessels, and
ease progression.83 Microglia/macrophages, however, may
are especially prominent near the boundaries between the
bodys external environment and the internal milieu, such as deliver trophic factors,84 and support myelin regeneration
the skin, mucosa of the lungs and digestive tract, as well as in by phagocytic removal of obstructive myelin debris85 or
the mouth, conjunctiva and nose through activation and recruitment of endogenous oligo-
7 Mast cells are also found within the nervous system, including dendrocyte precursor cells to the lesion site.86 Microglia
meninges, brain parenchyma and nerves. are found adjacent to amyloid deposits, and anti-inflam-
matory drugs that suppress the inflammatory response in
Physiology
microglia attenuate symptoms in a mouse model of Alz-
1 Key role in innate and acquired immunity heimers disease.87 Yet, in one study reducing or ablating
2 Upon activation rapidly release granules into the interstitium resident microglia failed to alter amyloid plaque load in
3 Degranulation is caused by direct injury (e.g. physical or transgenic mouse models of Alzheimers disease.88
chemical), cross-linking of IgE receptors or by activated com- Further, deleting the microglial chemokine receptor
plement proteins
CCR2 (which mediates the accumulation of mononuclear
4 Capable of elaborating a vast array of important cytokines
phagocytes at sites of inflammation) accelerated early dis-
and other inflammatory mediators
5 Express multiple pattern recognition receptors thought to be ease progression and impaired microglial accumulation in
involved in recognizing broad classes of pathogens an Alzheimers disease mouse model.89 Microglia activa-
6 Granules carry a variety of bioactive chemicals, proteoglycans, tion via TLR4 signalling appears able to reduce, to some
serine proteases, neuropeptides; can be transferred to adjacent extent, Ab deposits and preserve cognitive functions from
cells of the immune system and neurones via transgranulation Ab-mediated neurotoxicity.90 However, prolonged activa-
and their pseudopodia tion of microglia is likely to result in a pro-inflammatory
state. This idea is borne out in a newly published study
Role in disease
in which the authors used monophosphoryl lipid A
1 Allergic reactions (MPL), a lipopolysaccharide-derived TLR4 agonist that
2 Anaphylactic shock exhibits unique immunomodulatory properties at doses
3 Neuropathic and inflammatory pain that are non-pyrogenic.91 Repeated systemic injections of
4 Acute and chronic neurodegenerative disorders MPL, but not lipopolysaccharide, significantly improved
Alzheimers disease-related pathology in a transgenic
mouse model. Treatment with MPL led to a significant
reduction in Ab load in the brains of these mice, as well
Microglia and mast cells: the other side of the
as to enhanced cognitive function. MPL induced a potent
coin
phagocytic response by microglia while triggering only a
Activated microglia elaborate a potentially lethal cocktail moderate inflammatory reaction.114
of compounds capable of damaging neurons, oligoden- As discussed earlier, acute CNS injuries are marked by
drocytes or extracellular matrix molecules, and depletion a prolonged inflammatory response involving microglial
or blockade of microglia and macrophages prevents dis- activation and infiltration of macrophages and neutroph-
ils. However, the fact that microglia accumulation at the stress) can diffuse across several hundreds of microme-
lesion site and penumbra hints at a possible neuropro- tres to elicit a rise in Ca2+ in neighbouring cells.101
tective role. Indeed, genetic ablation of microglial cells ATP binding to P2 receptors may stimulate release of
results in a larger infarct after transient middle cerebral IL-33 from microglia pre-activated (primed) with
artery occlusion,92 while microglia injected into the PAMPs via TLRs.102 Interleukin-33 can induce mast
circulation of Mongolian gerbils home to an ischaemic cells to secrete IL-6, IL-13 and CCL2 in turn modu-
hippocampal lesion (facilitated by ischaemia-induced lating microglia activity. Other examples include mast
bloodbrain barrier compromise) and improve neuron cell tryptase cleavage/activation of proteinase-activated
survival.93 Further, microglia may protect hippocampal receptor 2 on microglia (resulting in P2X4 receptor up-
neurons from excitotoxicity.94 Resting (ramified) micro- regulation and brain-derived neurotrophic factor
glia respond to, and repair, subclinical abnormalities of release),103 while microglia-derived IL-6 and TNF-a up-
the brain without a complete activation transforma- regulate mast cell expression of proteinase-activated
tion,48 and are probably also key players in developmen- receptor 2, resulting in mast cell activation and TNF-a
tal synaptic pruning (discussed in more detail release.104,105 Elements of the complement system are
elsewhere95). also potential participants in this communication net-
Potential beneficial actions of mast cells should not be work, as the receptor for the chemoattractant C5a is
overlooked. Mast cells of human origin express and store markedly up-regulated on reactive astrocytes and micro-
angiogenin (a member of the ribonuclease A superfamily) glia in inflamed CNS tissue,106 C5a peptide is released
within their granules, which is released upon stimulation in neuroinflammation,107 and there is cross-talk between
by FceRI-mediated signals, TLR ligands and nerve growth C5a and TLR4; mast cell C5a receptor is up-regulated
factor.96 Nerve growth factor-stimulated human mast cells upon activation, and C5a receptor is a strong mast cell
release greater amounts of angiogenin compared with chemoattractant signal towards C5a peptide. These last
FceRI cross-linking. Human angiogenin is reported to be findings point to an additional element whereby micro-
neuroprotective and to promote the survival and neurito- glia and mast cells may work in concert to promote
genesis of motor neurons,97 and recent studies associating neuroinflammation (Table 2).
angiogenin gene mutations with ALS98 suggest a possible
disease link. Mast cells are a source of serotonin in the
Taping endogenous mechanisms as a therapeutic
hippocampus, which can contribute to behavioural and
approach to neuroinflammation
physiological functions in the hippocampus.99 Outside
the nervous system, mast cells may contribute to wound Targeting microglial and mast cell activation is emerging
healing.100 as a promising avenue for neuropathic pain,124 as well as
agents that inhibit neurotoxic glial cell activation.125
Given the dangers that neuroinflammation poses to the
A mast cellglia dialogue
organism, it would not be surprising if Nature has
Given their frequent proximity at sites of neuroinflam- endowed the body with the capacity for self-defence.
mation, and the potential for peripheral inflammation Indeed, we now recognize the existence of molecules
to influence supraspinal behaviours, it is conceivable involved in endogenous protective mechanisms that are
that lines of communication exist between these two activated following different types of tissue damage or
cell types. There is mounting evidence for this, which stimulation of inflammatory responses and nociceptive
will be briefly summarized here (see ref. 95 for a more fibres. For example, chronic inflammatory processes such
detailed discussion). There is growing interest in TLR as those sustaining neuropathic pain may be counteracted
signalling pathways in neurodegenerative disorders and by a programme of resolution that includes the produc-
neuropathic pain, and especially TLR2 and TLR4. tion of lipid mediators able to switch off inflammation.126
Engagement of TLR2/TLR4 on mast cells leads to Chronic inflammatory conditions may lower the levels or
release of cytokines that recruit immune cells to the actions of these molecules;127 conceivably, administration
sites of injury. Likewise, microglial recruitment depends of such lipid mediators might provide an avenue to com-
on signalling pathways involving TLR2/TLR4. Mast cell mandeer natures own anti-inflammatory mechanisms
activation will up-regulate chemokine expression, and induce a dominant program of resolution.128 One
including CCL5/RANTES, which induces a pro-inflam- interesting class of such natural mediators comprises the
matory profile in microglia. Microglia-released IL-6 and N-acylethanolamines (NAEs), which are composed of a
CCL5 could, in turn affect mast cell expression of fatty acid and ethanolamine the so-called fatty acid eth-
TLR2/TLR4. ATP, released from damaged cells/tissues, anolamines. Principal fatty acid ethanolamine family
is a potent stimulus for microglia in vitro. ATP may act members include the endocannabinoid N-arachidonoy-
as an autocrine/paracrine factor for mast cells, and ATP lethanolamine (anandamide) and its congeners N-stearoy-
released from one mast cell (e.g. FceR1 cross-linking, lethanolamine, N-oleoylethanolamine and N-palmitoy-
S. D. Skaper et al.
Table 2. Potential avenues of mast cellglia communication
Biological actions
Effector Microglia/astrocytes Mast cells References
TLR2, TLR4 Microglial release of IL-6 and CCL5 affects Up-regulation of cytokine/chemokine release; 81,108114
surface expression of TLR2/TLR4 on mast CCL5/RANTES induces pro-inflammatory
cells profile in microglia; recruitment of immune
cells to site of injury
ATP/P2 receptors ATP stimulates IL-33 release from microglia IL-33 binds to its receptor on mast cells and 101,102,115
pre-activated with PAMPs via TLRs induces secretion of IL-6, IL-13 and
monocyte chemoattractant protein 1 which,
in turn could modulate microglia activity
Proteinase-activated Mast cell tryptase cleaves/activates PAR2 on IL-6 and TNF-a from microglia can 101,104,105,116
receptor 2 (PAR2) microglia, resulting in P2X4 receptor up-regulate mast cell expression of PAR2,
up-regulation and BDNF release which can result in mast cell activation and
TNF-a release
CXCR4/CXCL12 Promotes microglia migration and activation; CXCR4 acts as mast cell chemotaxin 117120
CXCR4/CXCL12 are both up-regulated in
hypoxia/ischaemia
C5a receptor (C5aR) C5aR up-regulated upon microglia C5aR up-regulated upon activation; a strong 106,107,121
activation; C5a peptide released in mast cell chemoattractant signal towards
neuroinflammtion; cross-talk between C5a C5a peptide; cross-talk between C5a and
and TLR4 TLR4
CD40/CD40L Astrocytes display enhanced expression of Display enhanced surface expression of 122,123
CD40 cross-talk with CD40L leads to CD40L respectively cross-talk with CD40
production of inflammatory cytokines; leads to production of inflammatory
astrocyte-derived cytokines/chemokines cytokines
trigger mast cell degranulation
BDNF, brain-derived neurotrophic factor; IL, interleukin; PAMPs, pathogen-associate molecular patterns; PAR, proteinase-activated receptor;
TLR, Toll-like receptor; TNF-a, tumour necrosis factor-a. [Modified from Skaper et al.95 (Table 1), Copyright (2012), with permission from the
Federation of American Societies for Experimental Biology].
Palmitoylethanolamide
production increases with
stress from: Palmitoylethanolamide
Peripheral (STRESS) Resulting actions of

tissue inflammation N-APE Palmitoylethanolamide:
Anti- Figure 2. Palmitoylethanolamide synthesis and
Neuroinflammation inflammation catabolism. A plasma membrane-associated
Pain Neuroprotection N-acylated phosphatidylethanolamine-phos-
Plasma pholipase D (PLD) converts N-palmitoyl-
PLD
membrane Pain relief phosphatidyl-ethanolamine (N-APE) into pal-
mitoylethanolamide and phosphatidic acid.
Palmitoy-lethanolamide is metabolized to pal-
Palmitoylethanolamide mitic acid and ethanolamine by both fatty acid
amide hydrolase (FAAH, which also breaks
Palmitoylethanolamide is metabolized down other fatty acid amides) and the more
FAAH/NAAA by FAAH and NAAA into
Palmitic acid and Ethanolamine selective N-acyl ethanolamine-hydrolysing acid
amidase (NAAA). Tissue levels of palmitoyle-
Inner thanolamide increase in stressful settings such
membrane as peripheral tissue inflammation, neuroin-
Ethanolamine Palmitic acid flammation and pain. See text for further
details.
lethanolamine (PEA, or palmitoylethanolamide).129 PEA ways,130 the principal one involving a membrane-
and its congeners are formed from N-acylated phosphati- associated NAPE-phospholipase D which generates the
dylethanolamine (NAPE) by several enzymatic path- respective NAE and phosphatidic acid (Fig. 2).131 This
enzyme converts N-palmitoyl-phosphatidyl-ethanolamine stressors provoking, for example, inflammation.134 In fact,

into PEA. In the mammalian brain, NAEs are hydrolysed PEA is produced/hydrolysed by microglia and mast
by: (i) fatty acid amide hydrolase in the endoplasmic cells,135,136 it down-modulates mast cell activation,137 and
reticulum, which breaks down NAEs into the corre- controls microglial cell behaviours.138,139 Tissue levels of
sponding fatty acid and ethanolamine;132 (ii) lysosomal PEA are elevated in brain areas involved in nociception
NAE-hydrolysing acid amidase (NAAA) (Fig. 2).133 and in spinal cord following neuropathic pain induc-
NAAA is found mainly in macrophages, where it hydro- tion,140 as well as conditions associated with pain devel-
lyses NAEs with less than 18 carbon atoms, i.e. PEA, but opment138,141 and in the interstitium of the trapezius
not N-oleoylethanolamine and N-stearoylethanolamine. muscle of women with chronic widespread pain and
In contrast, fatty acid amide hydrolase hydrolyses all three chronic neckshoulder pain (Table 3).142 The above
NAEs. observations suggest that PEA maintains cellular
Molecules like PEA may, conceivably, function to homeostasis by acting as mediator of resolution of
maintain cellular homeostasis when faced with external inflammatory processes (Fig. 3). A corollary to this idea
Table 3. Changes in palmitoylethanolamide levels during neuroinflammation
Disease; tissue or body fluid Change Main finding References
Chronic relapsing experimental allergic ~Twofold increase 143

encephalomyelitis; spinal cord
Experimental acute stroke; striatal and cortical ~25-fold increase compared with controlateral (non-infarcted) 144
infarcted hemisphere areas
Experimental focal cerebral ischaemia; ischaemic 25-fold increase compared with sham-operated animals, at 24 hr 138
cerebral cortex post-focal cerebral ischaemia
Cerebral ischaemia in man; penumbral tissue Significantly increased levels within the first day after ischaemia 145
surrounding the primary ischaemic lesion
(microdialysis study)
Chronic migraine or probable chronic migraine and Significantly higher levels in the two patient groups 146
probable analgesic-overuse headache; cerebrospinal (without significant difference between them) compared
fluid with control subjects
Chronic widespread pain and chronic neckshoulder Significantly higher levels compared to healthy subjects, 142
pain in women; microdialysis dialysate of the and correlation with pain intensity
trapezius
Table 4. Preclinical studies showing anti-neuroinflammatory and/or neuroprotective effects of palmitoylethanolamide
Model Action References
Compression model of spinal cord trauma in mice Reduces spinal inflammation/tissue injury, 147,148
ameliorates recovery of motor limb function
Limits mast cell infiltration and activation; reduces
activation of microglia and astrocytes
Traumatic brain injury in mice Reduces edema and infarct size 149
Improves neurobehavioural functions
MPTP mouse model of Parkinsons disease Protects against MPTP-induced neurotoxicity, 150
microglial and astrocyte activation, and functional deficits
Stroke (middle cerebral artery occlusion in rats) Reduces oedema and infarct size 151
Improves neurobehavioural functions
b-Amyloid peptide injection in rat brain Counteracts reactive gliosis 152
Reduces behaviour impairments
Chronic constriction injury in sciatic nerve Anti-allodynic and anti-hyperalgesic effects 153155
Reduces mast cell activation
Preservation of nerve structural integrity
Acute inflammation (formalin, dextran, Reduces mast cell activation, tissue oedema, 156161
carrageenan injection in rat hindpaw) inflammatory/mechanical hyperalgesia
WAG/Rij rat model of absence epilepsy Anti-epileptic action 162
MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
S. D. Skaper et al.
Sham MPTP MPTP+PEA designed to improve bioavailability) in the treatment of

~47 000 various syndromes associated with chronic pain that is
GFAP
poorly responsive to standard therapies.169 Some 40 or so
-actin clinical trials have been conducted to date, with a patient
base exceeding 2000.170 There has also been a case study
10
Densitometric units
GFAP/-actin ratio
*** reporting on the effects of ultramicronized PEA in spo-

radic ALS, in which treatment led to an improved clinical
(OD*mm2)
5 picture, as evidenced by electromyographic analysis and

###
pulmonary function.171 A more detailed description of
0
PEA clinical trials will be discussed elsewhere (Skaper
Sham MPTP MPTP+PEA S.D., unpublished data). Importantly, PEA has no adverse
effects at pharmacologically relevant doses.
Figure 3. Palmitoylethanolamide (PEA) treatment reduces activation What is the molecular basis underlying the effects of
of astrocytes induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
PEA? As suggested in a number of studies, PEA may be a
dine (MPTP) injection. Western blot analysis showed a significant
ligand for peroxisome proliferator activated receptor a
expression of glial fibrillary acidic protein (GFAP) in the substantia
nigra. PEA treatment significantly reduced the activation of astro-
(PPARa), one of a group of nuclear receptor proteins
cytes after MPTP injection. The relative expression of the protein that function as transcription factors regulating the
band (~47 000 molecular weight) was standardized for densitometric expression of genes. The a- and c-isoforms of PPAR in
analysis to b-actin levels, and reported as mean SEM from n = 5 particular are associated with pro-inflammatory events.
or n = 6 brains for each group. ***P < 0001 versus sham, PEA actions (anti-inflammatory,172 anti-nociceptive/anti-
###
P < 0001 versus MPTP + vehicle. Modified from Esposito neuropathic155,161,173 and neuroprotective150,154,174) were
et al.150(Figure 10, Esposito et al. This is an open-access article either absent in PPARa null mice or blocked by PPARa
distributed under the terms of the Creative Commons Attribution antagonists. An entourage effect has also been hypothe-
License). sized to explain the pharmacological actions of PEA,
whereby PEA enhances the anti-inflammatory and anti-
nociceptive activity of other endogenous compounds by
is that pathological situations may arise in which endoge- potentiating their affinity for a receptor or by inhibiting
nous PEA levels are inadequate to deal with the ensuing their metabolic degradation.175 Anandamide is a candidate
insult. In these cases, exogenous administration to effec- molecule, as it possesses anti-inflammatory and anti-noci-
tively top up the bodys own supply may be a therapeu- ceptive effects. Anandamide and its congeners like PEA
tically viable approach. Indeed, a growing number of have in common the transient receptor potential vanilloid
studies demonstrate the validity of such; these are briefly type 1 (TRPV1) receptor. The TRPV1 receptor, a non-
summarized in Table 4. A more detailed discussion is selective cation channel expressed in small diameter sen-
outside the scope of the review, and will be covered sory neurons, is activated by noxious heat, low pH and
elsewhere (Skaper S.D., unpublished data). capsaicin. Anandamide itself is a TRPV1 receptor agonist,
As NAAA preferentially hydrolyses PEA, inhibition of and PEA enhances anandamide stimulation of the human
its degradation represents a complementary therapeutic TRPV1 receptor176 in a cannabinoid CB2 receptor antago-
approach to treat inflammation. A number of selective nist-sensitive fashion (although PEA shows no appreciable
NAAA inhibitors have been described to date;163165 these affinity for either CB1 or CB2 receptors) which could be
dampen responses induced by inflammatory stimuli in interpreted as PEA acting indirectly by potentiating
vivo and in vitro, and elevate PEA levels in vitro as well.163 anandamide actions.157 Mast cells177 and microglia178
The most recently identified compound, 1-(2-biphenyl-4- reportedly express TRPV1 receptors.
yl)ethyl-carbonyl pyrrolidine, is a reversible and competi-
tive NAAA inhibitor: it reduces mRNA expression levels
Concluding remarks
of inducible nitric oxide synthase and IL-6 and increases
intracellular PEA levels in mouse macrophages upon lipo- Neuroinflammatory disorders are conditions where
polysaccharide-induced inflammation.166 immune responses damage components of the nervous
The numerous preclinical studies have encouraged clin- system (Karolinska Institute, 2013; www.ki.se). Inflam-
ical trials of PEA, mainly in the area of chronic and neu- matory effectors derive from the innate and adaptive
ropathic pain. PEA reportedly improved myelinated-fibre immune systems, as well as glia within the CNS. Micro-
function in patients with chemotherapy-induced painful glia, in particular, act as sensors for disturbed brain tis-
neuropathy,167 and reduced neuropathic pain in a patient sue homeostasis and accumulate locally in response to
with multiple sclerosis.168 A recently presented case series neuronal cell injury or entry of foreign material in the
described the application and potential efficacy and safety brain.179 Few studies until now have been directed to
of micronized and ultra-micronized PEA (formulations resident brain cell types capable of mounting immediate
host responses in the brain and meninges. Mast cells are Further, they provide at best transient relief in only a
effector cells of the innate immune system, and repre- fraction of neuropathic pain patients and can produce
sent the first responders to injury rather than micro- serious CNS side effects. Agents like cromolyn, which sta-
glia.51 Mast degranulation/mediator release is very rapid, bilize mast cells, suppress development of hyperalgesia
while longer lasting activation elaborates de novo formed but do not affect microglia. Microglial inhibitors (e.g. mi-
mediators. Mast cell degranulation does not result in nocycline) commonly used in pain models rely on their
cell demise; rather, mast cells are stable, multiple-use anti-inflammatory properties but may suffer from issues
cells capable of surviving and delivering several consecu- such as non-selectivity in targeting one cell population, as
tive hits.180 well as the risk of acute or cumulative toxicity. Incom-
Research to-date has largely focused on detrimental plete understanding of mechanisms underlying the induc-
effects of neuroinflammation in association with psychiat- tion and maintenance of neuropathic pain has hindered
ric and neurodegenerative diseases, as well as neuropathic more effective treatments, including elucidating the role
pain. Yet, we know little of glial and mast cell changes in of mast cells and how they might interact with microglia.
human chronic pain unequivocal demonstration that Clearly, much remains to be learned about signalling
glial and mast cell activation occurs in hypersensitized mechanisms that regulate neuroinflammation. One may
patients remains an important gap. We lack also system- envision the CNS neuron being subjected to assault by a
atic studies that provide a correlation between the magni- microgliaastrocytemast cell network, as a result of inad-
tude of glial and/or mast cell markers in cerebrospinal equate regulation of these non-neuronal cells because of
fluid or spinal tissue and the intensity of pain in patients. excessive and/or persistent exogenous and/or endoge-
Todays armamentarium to combat neuropathic pain nous stimuli, and/or an inadequate cellular inhibitory
(antidepressants, anticonvulsants, sodium channel block- capacity (Fig. 4). Targeting endogenous regulators of
ers, glutamate receptor antagonists, opioids) treats the neuroinflammation may therefore prove to be a viable
symptoms but not the underlying pathophysiology. strategy for affecting a diverse array of nervous system
disorders. Within this context, the capacity of PEA to
modulate the protective responses of animals during
(ST inflammation and pain led to the hypothesis that endoge-
RE
SS
)
nous PEA may be a component of the complex homeo-
Astrocyte static system controlling the basal threshold of both
Microglia
inflammation and pain. The production of PEA during
Central inflammatory conditions supports this role, and emerging
neuron data that selective inhibition of PEA degradation is anti-
inflammatory provides more direct evidence for the
involvement of PEA in the control of pain and inflamma-
Mast cell tion. It also leads one to ponder if we are not missing
important therapeutic avenues by studying glia and mast
cells in isolation from each other. Future studies should
investigate the role of mast cells in inflammatory diseases
Degranulation Activation and as a network, which requires a critical examination of
and/or transgranulation proliferation
in brain parenchyma specific tissue localization, function and dynamic interac-
Phenotypic tion with endogenous cells.
transformation
Abnormal release of: with abnormal release of:
Disclosures
Inflammatory Neurotrophic Inflammatory Neurotrophic
cytokines factors cytokines factors The authors declare no conflicts of interest.
Other mast cell

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doi:10.1111/imm.

12170 REVIEW SERIES ON IMMUNE RESPONSES IN NEURODEGENERATIVE DISEASES

Mast cells, glia and neuroinflammation: partners in crime?

OTHER ARTICLES PUBLISHED IN THIS SERIES

Stephen D. Skaper, Laura Facci and Summary

metabolism and behaviour including the expression of

Neuropathic pain Ischaemia and traumatic brain injury

Box 1. Mast cell ID chart

Origin and classification

1 First described by Paul Ehrlich in 1878 on the basis of their

Table 2. Potential avenues of mast cellglia communication

Effector Microglia/astrocytes Mast cells References

Peripheral (STRESS) Resulting actions of

enzyme converts N-palmitoyl-phosphatidyl-ethanolamine stressors provoking, for example, inflammation.134 In fact,

Table 3. Changes in palmitoylethanolamide levels during neuroinflammation

Disease; tissue or body fluid Change Main finding References

Chronic relapsing experimental allergic ~Twofold increase 143

Table 4. Preclinical studies showing anti-neuroinflammatory and/or neuroprotective effects of palmitoylethanolamide

Model Action References

Sham MPTP MPTP+PEA designed to improve bioavailability) in the treatment of

*** reporting on the effects of ultramicronized PEA in spo-

5 picture, as evidenced by electromyographic analysis and

Other mast cell

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