Mast cells in brain inflammation
There is growing interest is the presence of MCs in meningiomas, because of the conflicting reports with regard to the association of MCs with meningioma grade [
24,
29,
30]. Furthermore, there is increasing evidence suggesting MCs may stimulate neoplastic growth [
31,
32], while others support a potential dual role of MCs contributing both to tumorigenesis and tumor-suppression processes in various types of cancers [
33].
MCs originate from a bone marrow progenitor and subsequently develop different phenotype characteristics locally in tissues. Their range of functions is wide and includes participation in allergic reactions, innate and adaptive immunity, inflammation, and autoimmunity [
34]. In the human brain, MCs can be located in various areas, such as the pituitary stalk, the pineal gland, the area postrema, the choroid plexus, thalamus, hypothalamus, and the median eminence [
35]. In the meninges, they are found within the dural layer in association with vessels and terminals of meningeal nociceptors [
36]. MCs have a distinct feature compared to other hematopoietic cells in that they reside in the brain [
37]. MCs contain numerous granules and secrete an abundance of prestored mediators such as corticotropin-releasing hormone (CRH), neurotensin (NT), substance P (SP), tryptase, chymase, vasoactive intestinal peptide (VIP), vascular endothelial growth factor (VEGF), TNF, prostaglandins, leukotrienes, and varieties of chemokines and cytokines some of which are known to disrupt the integrity of the blood-brain barrier (BBB) [
38‐
40].
They key role of MCs in inflammation [
34] and in the disruption of the BBB [
41‐
43] suggests areas of importance for novel therapy research. Increasing evidence also indicates that MCs participate in neuroinflammation directly [
44‐
46] and through microglia stimulation [
47], contributing to the pathogenesis of such conditions such as headaches, [
48] autism [
49], and chronic fatigue syndrome [
50]. In fact, a recent review indicated that peripheral inflammatory stimuli can cause microglia activation [
51], thus possibly involving MCs outside the brain.
Mast cells in meningiomas
MCs have been found to infiltrate both primary and metastatic tumors [
52]. For instance, MCs infiltrated and proliferated both in the tumor mass and in the area adjacent to tumor-associated vessels in an experimental model of high-grade gliomas, including glioblastoma multiforme [
53]. In addition, stem cell factor (SCF), the main growth factor of MCs, was mainly expressed around the tumor-associated vessels, and it was proposed that the tumor-derived CXCL12/CXCR4 attracted MCs [
53].
Polajeva et al. reported that MCs were detected in both low- and high-grade gliomas [
54], and it was concluded that (a) MC accumulation in these tumors increased as grade malignancy increased, (b) neutralization of the glioma-derived macrophage migration inhibitory factor (MIF) reduced the extent of MC migration, (c) the magnitude of MC recruitment correlated with the level of MIF, and (d) MIF-induced accumulation of MCs in vivo was associated with activation of the signal transducer and activator of transcription 5 (STAT5) [
54]. Additionally, MCs have been detected in increased numbers in the infiltrating zones of medulloblastomas and gliomas [
55], while they were also found to be erythropoietin (EPO)-positive in 50 % of a series of hemangioblastoma specimens [
56].
Moreover, it has been proposed that metastatic brain tumors can be promoted by stress (unavoidable in patients with cancer) [
57] which activates brain MCs to disrupt the BBB via the CRH pathway [
58]. This increases BBB permeability for primary cancer cells deriving from the periphery, which can subsequently infiltrate brain parenchyma and metastasize as was shown for rat mammary adenocarcinoma [
59]. In two case reports, breast cancer cells were reported to be associated with meningiomas [
60,
61] and breast cancer may be concurrent with meningiomas [
62]. Immune responses, such as the peritumoral collection of MCs, are increasingly considered to augment tumor growth and metastasis [
33,
57,
63].
Two retrospective studies [
24,
29] evaluated MCs, by tryptase immunostaining, in a series of meningiomas of various grades. Specimens were divided in two groups of low-grade meningiomas (WHO grade I) and high-grade meningiomas (WHO grades II and III). In the first study [
24], 70 cases were analyzed. In the group of low-grade tumors (
n = 63), MCs were seen in 20/63 cases (31.8 %), with strong diffused immunoreaction in 8/20 mostly next to blood vessels disseminated intratumorally; all psammomatous, secretory, and meningothelial meningiomas were negative for MCs, whereas all fibrous and transitional meningiomas were positive. Interestingly, CT brain images of all MC-positive low-grade meningiomas showed marked peritumoral edema [
24].
In the second group (
n = 7), 6/7 (86 %) tumors were positive for MCs and all presented with peritumoral edema on CT. One anaplastic meningioma was strongly immunopositive, while the rest of the high-grade meningiomas showed focal, but disseminated, positive immunoreaction for tryptase [
24]. The second study [
29], was conducted on 154 cases, and apart from MCs, it also evaluated the expression of hypoxia-inducible factor-1 (HIF-1), which is a marker of hypoxia found to be correlated with grade and progression of many cancers including glioblastoma [
64]. In the group of low-grade meningiomas (
n = 104), MCs were seen in 42 cases (40.4 %), with strong diffused immunoreaction in 17/42. In the group of high-grade meningiomas (
n = 50), 45 (90 %) of tumors were positive for MCs, with strong immunoreaction in 6/45 cases. MCs were observed not only next to blood vessels but also within the tumor [
29].
Based on the Steinhoff classification of peritumoral edema [
65], this study showed a statistically significant association between HIF-1 expression, tryptase expression, and the presence of peritumoral brain edema, as well as between MC accumulation and HIF-1 expression based on meningioma grading [
29]. MC mediators such as histamine, serotonin, or VEGF might significantly contribute to the formation of peritumoral edema.
Tirakotai et al. studied secretory meningiomas (grade I), which were found to be infiltrated by a higher number of MCs compared to other types (nonsecretory meningiomas). Higher number of MCs was found mainly in and around the pseudopsammoma bodies of secretory meningiomas [
66] Eparil et al. and Tina-Suck et al. investigated 12 and 10 cases, respectively, of chordoid meningiomas (grade II) [
67,
68]. Both reported a significant number of MCs in this meningioma variant. The first observed MCs both within the myxoid stroma and the epithelial cell islands, by using toluidine blue and Giemsa stains, in 100 % of cases. MCs were sparsely populated, granulated, single in arrangement, and more frequently seen at the interface regions [
67]. The second observed MCs present both in the connective tissue stroma and the epithelial cell islands in all specimens, using positive Periodic Acid Schiff (PAS) and mucicarmine stains [
68]. In contrast, another study [
30] reported that MCs had poor associations with meningioma tumor grading.
Meningiomas and perivascular edema
Cerebral edema is quite common in intracranial meningiomas. In one study of 68 meningiomas evaluated by computed tomography, 40 % had significant edema [
71]. Another review concluded that intracranial meningiomas were associated with brain edema in 50–66 % of cases [
72]. In fact, edema has been considered a prognostic factor for meningiomas and metastases, but not gliomas [
73]. Moreover, there was a strong correlation between brain edema and shape of tumor margins and signal intensity on magnetic resonance imaging of 51 meningiomas studied [
74]. Peritumoral edema may be due to increased expression of vascular endothelial growth factor (VEGF) [
75,
76]. In fact, meningiomas can secrete VEGF-A themselves [
77]. It is of interest that MCs can secrete large quantities of VEGF especially in response to CRH [
78], which can be secreted by MCs [
79] and by metastatic cancer cells [
80].
Meningiomas are well known to present with severe headaches, even when tumors are small with little edema, and mass effect alone is insufficient to account for this symptom [
81,
82]. It is therefore of interest that MCs have been implicated in the pathogenesis of migraines [
38] and meningeal MC-neuron interactions are increasingly invoked in the pathophysiology of headaches [
83,
84]. Meningeal inflammation was also regarded critical in seizures [
85], and there have been a number of cases of patients with seizures due to underlying mastocytosis [
46,
86].
The association of MCs with perivascular edema is also important because it may indicate disruption of the BBB, which worsens by stress and contributes to brain metastases [
57], multiple sclerosis [
87], autism [
35,
88], and brain “fog” [
89]. It may, therefore, be important to investigate the presence of occult meningiomas in such disorders.
Treatment options
Brain edema may be reduced with the use of glucocorticoids or anti-angiogenic therapy [
77].
Cyclooxygenase (COX) inhibitors have also been considered for the treatment of brain edema [
73,
90] especially because COX-2 expression has been reported in astrocyte and microglia in humans [
91]. It is of interest that certain natural flavonoids, such as quercetin (3, 5, 7-3΄ 4΄-pentahydroxyflavone), inhibit COX-2 and angiogenesis [
92,
93], and its structural analog luteolin (5,7-3′4′-tetrahydroxyflavone) inhibits COX-2 in glioblastoma cells [
94]. Quercetin also has antiproliferative activity against human meningiomas [
95] and gliomas [
96,
97]. Luteolin has synergistic action with COX-2 inhibitors on inducing apoptosis of breast cancer cells [
98].
Both quercetin [
99] and luteolin inhibit MCs [
99‐
101], especially MC-derived VEGF release. Luteolin also inhibits activation of auto-immune T cells [
102,
103].
A methylated luteolin analog (6-methoxyluteolin) was shown to inhibit IgE-stimulated histamine release from human basophilic KU812F [
104]. Moreover, we recently showed that tetramethoxyluteolin is a more potent inhibitor of human cultured MCs than luteolin [
105].
Luteolin also inhibits activation and proliferation of microglia [
106‐
109], which have been implicated in autism [
110]. A luteolin/quercetin-containing formulation in olive fruit oil significantly improved attention and behavior in children with autism [
111,
112]. It is interesting that oleocanthal present in olive oil was shown to have COX inhibitory activity [
113].
Flavonoids are naturally occurring compounds found mostly in green plants, herbs, and seeds with potent antioxidant, anti-inflammatory, and anticancer properties [
114]. Recent reviews have discussed the use of flavonoids in neuropsychiatric [
115,
116] and neurodegenerative [
117,
118] diseases, especially luteolin in the prevention and/or treatment of brain fog [
119].