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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4408_Библиотеки_им_академика_М_И_Перельмана
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H. Sudho and M. Schürmann
broblasts. These molecules amplify the inammatory signal and transmit it back into the extracellular space. These
mediators will modulate the inammatory response, and
regulate the maturation, growth, and responsiveness of particular cell populations. Extracellular signaling through
cytokines expressed upon the initial immune response are
able to induce the secretion of cytokines into the extracellular space and induce further inammatory signaling in a
paracrine or autocrine manner. In the following subchapter,
we want to explain the expression and role of different cytokines highly expressed in cholesteatoma tissue.
Probably, the most prominent cytokine the tumor necrosis
factor alpha (TNF-α) is known as a potent inducer of inammation and apoptotic cell death. It is strongly expressed upon
activation of the transcription factors NF-κB and AP-1.
Hence it is not surprising that TNF-α can be induced in, e.g.,
monocytes after incubation with cholesteatoma debris containing high levels of LPS [100]. It is not surprising that there
is a strong correlation between TNF-α and severity of infection in acquired cholesteatoma [101]. In vivo the expression
level of TNF-a was compared to different tissue types and
was found to be signicantly higher in tissue from cholesteatoma [101–104]. Even the serum level of TNF-α was
increased in patients with cholesteatoma than those without
inammatory middle ear diseases [105, 106]. In cholesteatoma, the expression of TNF-α is widely distributed. It was
localized in the connective tissue and particularly in macrophages residing in the cholesteatoma perimatrix [104].
Notably, cholesteatoma matrix and perimatrix express high
levels of TNF-α [103]. In accordance with these in vitro
studies, epidermal cholesteatoma cells produced higher
amounts TNF-α than regular keratinozytes [107, 108].
Cholesteatoma keratinocytes expressed higher levels of
TNF-α than their healthy auditory canal skin counterparts,
which results in a positive feed forward loop further enhancing the already upregulated TNF-α concentration [108].
TNF-α was also found in the tissue adjacent to bone resorption areas in human and experimental middle ear cholesteatomas, where it was localized to mononuclear cells,
macrophages, broblasts, osteoblasts, and osteoclasts [109].
Interestingly, TNF-α was demonstrated to stimulate osteoclast formation in vivo [110]. In vitro TNF-α stimulated
monocytes to form multinucleated cells expressing osteoclast marker and was capable of stimulating macrophages to
produce acid phosphatase and collagenase leading to bone
resorption [109] (Fig.43.3). In alignment with this mechanism, several studies found that the TNF-α levels in cholesteatoma patients with bone destruction were higher than in
those without bone destruction [101, 105, 111–113]. TNF-α
is also able known to promote the proliferation, protein synthesis, and terminal differentiation of basal keratinocytes,
resulting in another clinical feature of cholesteatoma disease,
the accumulation of keratin debris [104]. Utilizing the supernatant of cholesteatoma cells Kato and co-workers could
demonstrate that TNF-α compromised ciliary activity and
mucociliary clearance of the Eustachian tube in the guinea
pigs [114]. Clinically, this would further aggravate the situation of the middle ear cavity. In contrast to role of TNF-α, the
density of the TNF-α receptor could not be correlated with
the degree of inammation or bone destruction present in the
acquired middle ear cholesteatoma [115].
Another important group of cytokines is interleukin
1-alpha and interleukin 1-beta (IL-1α and IL-1β). They are
both ligands of the two IL-1 receptors (IL-1-R) inducing pro-
Fig. 43.3 The contribution of
different inammatory
modulators to the
pathogenesis of cholesteatoma
disease. Shown are the
pathogenic symptoms
characteristic for
cholesteatoma disease (bold
letters) right next to their
modulators upregulated in
cholesteatoma tissue
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inammatory immune responses. IL-1 s are produced predominantly by macrophages but also by epithelial cells
widely present in cholesteatoma tissue. Their expression is
induced by the transcription factor NF-κB induced upon
stimulation with, e.g., PAMPs, DAMPs, or TNFs. According
to this, it is not surprising that IL-1α as well as IL-1β are
upregulated in cholesteatoma compared to healthy middle
ear epithelium [116], normal skin [46, 101], auditory canal
skin [103, 117] and even tissue from otitis media patients
[102]. Corresponding to the common of IL-1s expression in
epithelial cells, immunohistochemistry [116, 118] and in situ
hybridization [17] demonstrated that all cellular layers of
cholesteatoma epithelium stained strongly and uniformly for
Il-1 alpha and IL-1 beta. In the stroma of the cholesteatoma
intensely IL-1 s-positive cells belonging to the monocyte
macrophage lineage were detected by immunohistochemistry and in situ techniques [46, 118]. In alignment with these
observations invitro experiments demonstrated that keratinocytes but not broblasts secreted an enhanced amount of
IL-1α as well as IL-1β when compared to the same cell
derived from auditory canal skin [119]. Apart from the elevated expression of IL-1s, the corresponding Interleukin-1
receptor (IL-1R) were 3 times upregulated in cholesteatoma
and cholesteatoma keratinocytes compared to the same cell
in regular aural skin [120]. Adding to that the upregulation of
the IL-1 s the interleukin-1 receptor antagonist (IL-1-RA)
showed an elevated concentration in skin samples [117].
Further IL-1α stimulates keratinocytes and macrophages,
abundantly present in cholesteatoma tissue, to secret
additional IL-1α. All this will positively enhance the already
robust pro-inammatory IL-1 signaling in the already heavily inamed cholesteatoma tissue. IL-1α stimulates osteoclast formation [110] and is correlated to the expression of
MMP-9in cholesteatoma tissue [121]. IL-1 signaling is suggested to play an aggravating role in cholesteatoma induced
bone resorption. Several studies could prove a positive correlation between IL-1α and bone resorption [111, 112, 122].
Even though IL-1α is known to stimulate proliferation in
broblastic [123] and epidermal cells [124] no correlation
between IL-1α and proliferation marker cell nuclear antigen
could be detected [121].
Cytokine IL-6 is also increased in cholesteatoma tissue
[46, 103] as compared to regular skin [46]. IL-6 was mainly
localized in cholesteatoma epithelium as well as subepithelial stroma [103]. Studies comparing cholesteatoma keratinocytes with skin keratinocytes demonstrated, that this
elevated expression was preserved even after invitro cultivation [114, 125].The corresponding IL-6 receptors were
mainly found in the epidermis of inamed cholesteatoma
[126]. Downstream of the IL-6 receptors are the activating
STAT3 transcriptional factor and the inhibitory SCOS3 proteins. Fanglei etal. found that STAT3 is overexpressed, while
SOCS3 is downregulated in cholesteatoma epithelium [127]
and that STAT3 and SOCS3 were even negatively correlated
in the middle ear cholesteatoma. In accordance, the phosphorylated STAT3, the activated form of the transcriptional
factor, was signicantly higher in cholesteatoma epithelium
than in external auditory canal skin. This is suggesting that
abnormal IL-6 signaling in the middle ear cholesteatoma
may be involved in hyperproliferation and antiapoptosis of
cholesteatoma epidermal cells and hence promotes its formation. Several invivo studies detected a correlation between
IL-6 activity in cholesteatoma and bone erosion [103, 112,
122] . Even correlation between IL-6 serum level and bone
erosion was ascertained in cholesteatoma patients [128].
Only a single study was not able to link pSTAT3 to the degree
of bone destruction [129]. Notably, IL-6 was also proven to
negatively inuence the middle ear clearance by inhibiting
the ciliary activity in a guinea pig model [114].
The chemokine IL-8 also known as CXCL-8 is also
expressed in cholesteatoma tissue and might play a role in
cholesteatoma progression. Expression of IL-8 is signicantly higher in cholesteatoma tissue [79] or external auditory canal skin or postauricular skin [130]. This is in
accordance with the upregulation of id1 in cholesteatoma,
which is known to positively regulate IL-8 via different
molecular mechanisms [93]. The localization of IL-8 was
conned to the basal and suprabasal cell layer of the cholesteatoma matrix [131]. This is resembled in the invitro situation, where another study compares the expression of
cholesteatoma cells to normal skin cells. They described an
elevated expression of IL-8 stayed under culture conditions
in keratinocytes but absent in broblasts [119]. Cholesteatoma
keratinocytes reacted to an increase secretion of IL-8 upon
stimulation with TNF-α compared to their healthy counterparts [108]. Since TNF-α is highly expressed in cholesteatoma microenvironment, the invivo situation of high IL-8
expression in keratinocytes might be further increased by
TNF-α sensitivity. Since IL-8 is commonly expressed in
inamed cholesteatoma tissue, e.g., via HMGB1/RAGE
upregulated in cholesteatoma [42]. As it mainly acts on neutrophils that are infrequent in cholesteatoma tissue, its role in
generation of inltrate and/or pathogenesis is not fully
understood.
The cytokine granulocyte-macrophage colony- stimulating
factor (GM-CSF) can be initial induced through PRR.It is
not surprising that the expression level of GM-CSF of cholesteatoma epithelial tissue is higher in comparison to normal external auditory meatal skin epithelial tissue [132,
133]. Beyond that it is located in the peribasal area, in some
suprabasal cells of the epithelium, and in the inammatory
connective tissue, especially in the monocytes and broblasts [133]. Particularly its association with broblasts
might be of importance for cholesteatoma development since
its well documented role in proliferation, protein synthesis,
and terminal differentiation of keratinocytes [133].
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H. Sudho and M. Schürmann
Interestingly, in normal wound healing, the expression of
IL-1s in keratinocytes results in an induction of GM-CSF in
dermal broblasts which further increases the expression
ofIL-1s in keratinocytes. This positive feedback loop, which
results in health restoration of the epithelial barrier during in
normal wound healing, might be spin out of control in the
case of cholesteatoma tissue. Because the PRR-induced
overexpression of IL-1 s in cholesteatoma keratinocytes
[119] and GM-CSF in cholesteatoma broblasts might tilt
the equilibrium in this feedback loop. In accordance to that
invitro studies showed that broblasts derived from healthy
skin showed a much weaker expression of GM-CSF after
stimulation by IL-1α and/or IL-1β compared to cholesteatoma broblasts [134]. The less prominent macrophage colony- stimulating factor and the macrophage-colony-stimulating
factor were found to be overexpressed in cholesteatoma
specimens compared to normal external meatal skin [135]. It
was found to be located in the cholesteatoma perimatrix and
is released from activated T-cells in response to the inammatory process [135]. Since M-CSF is essential for osteoclast formation [136], it can be assumed that its role in the
pathogenesis is linked to the promotion of osteolytic properties of cholesteatoma.
Besides all these cytokines are released by various cells
upon PRR stimulation, mast cells frequently found in cholesteatoma tissue release not only cytokines but also various
other inammatory mediators via degranulation upon stimulation of their PRR.One of these mediators is histamine an
organic compound involved and able to increase blood ow
and vessel permeability. Another one is Heparin which is of
particular interest in cholesteatoma disease, since it enhances
the activity of heparin-binding EGF-like growth factor
(HB-EGF) . HB-EGF is the predominant growth factor in the
epithelialization required for cutaneous wound healing
[137]. Compared to normal post auricular skin, HB-EGF is
upregulated in cholesteatoma, where it is suspected to play a
major role in the excessive growth of epithelium and even
bone resorption [138].
The signaling most excessively investigated pathway is
the RANK-RANKL-OPG system. Briey, the RANKRANKL- OPG system is the major modulator of bone resorption. The receptor activator of nuclear factor κ B (RANK)
positively regulates osteoclast differentiation and activation
upon binding of its ligand (RANKL), while osteoprotegerin
(OPG) on the other side is a decoy receptor for RANKL and
hence negatively regulates the osteolysis. RANKL-positive
cells and/or the ratio of RANKL/OPG in cholesteatoma were
signicantly higher than that in external meatal skin [139,
140] postauricular skin [141] normal skin [142], auditory
canal skin, and even granulation tissues [139]. The expression of RANKL and RANK was localized mainly in the
broblasts [46, 140] and CD4-positive activated T-cells [89,
135] in the perimatrix and in the cholesteatoma epithelium
[143]. Clinically the increased RANKL expression positively correlated with inammatory markers [144], cholesteatoma progression [143], and osteolysis [145]. Interestingly,
few patients showed an upregulation of OPG-positive cells
[140] in their cholesteatoma matrix, which was demonstrated
to negatively correlated with the of degree of bone resorption
[145]. The expression of OPG in the matrix of cholesteatoma
might put resistance against the osteolytic RANKL signaling
in some cholesteatoma patients. In vitro data on cholesteatoma epithelia cells suggests that this pathogenic expression
of RANKL is induced by stimulation of the TLR4 by LPS
[146]. In agreement with this, a TLR4 knockdown in an animal model of acquired cholesteatoma reduced the amount of
osteoclast formation [64]. In contrast to this, clinical data
showed no correlation between RANKL expression and bacterial infection of the cholesteatoma [147]. It can be assumed
that this contradiction is partly caused by the low prevalence
of Gram (−) bacteria in this study (only 15%). In most cases,
the induction of RANKL expression in cholesteatoma is
probably rather linked to the high concentration of DAMP
able to stimulate TLR4 signaling anyway. Another way to
stimulate the expression of RANKL was detected by another
research group. They found that microRNA miRNA-17 was
present in the exosomes of cholesteatoma keratinocytes and
is able to upregulate the expression of RANKL in broblasts
and thereby promote osteoclast differentiation. Hence, they
concluded that miRNA-17 secreted by keratinocytes in
patients with middle ear cholesteatoma can upregulate the
expression of RANKL in broblasts and induce osteoclast
differentiation and bone destruction [148].
Apart from bone destruction, the deposition of extracellular matrix is another pathogenic character of cholesteatoma. The cytokine transforming growth factor beta 1
(TGF-β1) is one of the major inducers of ECM deposition. It
was demonstrated that the expression of TGF-β1in cholesteatoma is upregulated compared to that in normal post aural
skin [149]. The expression of TGF-β1 was localized in broblastic as well as in lymphoid cell residing in the perimatrix
[150]. Additionally, the negative regulator of TGF-β1 signaling Smad7 was signicantly reduced, and the positive regulator pSMAD2 was enhanced in cholesteatoma epithelial
and stromal cells in relation to the same cell types derived
from tissue of the retro auricular skin [151]. This upregulation of TGF-β1 signaling can be linked to the expression of
tenascin, bronectin, and collagen brils characteristic for
stromal brosis [150]. Another interesting study demonstrated that not only bronectin but also its embryonic form
generated by alternative splicing that bears the extra domain
A-positive bronectin (EDA-FN) correlated with the localization of TGF-β1 and another positive regulator of TGF-β1
signaling SMAD3 [152]. Since it is known, that EDA-FN
expression is induced via TGF-β1 signaling after wound
injury [153], this correlation is not surprising. Unfortunately,
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EDA-FN is an endogenous ligand for TLR-4 and will therefore further enhance the TLR-4-driven inammatory state of
cholesteatoma tissue. This will lead to a further recruitment
of Th1 cells known for their ability to secrete high amount of
EDA-FN upon TGF-β1 stimulation [154]. All this will lead
to another positive feedback mechanism perpetuating the
devastating exaggerated inammatory state in cholesteatoma
tissue. Apart from this ECM-based pathogenesis, TGF-β1
also induces tissue degeneration. For example, a positive
correlation between metalloproteases-1 (MMP-1) and TGFβ1 could be detected in cholesteatoma but not in skin of
external auditory meatus [155]. Another major enzyme in
cholesteatoma-induced tissue degradation the MMP-9 was
induced in external ear canal skin keratinocytes by TGF-β1
derived from cholesteatoma debris and granulation tissue
extract [156]. In contrast to that, this correlation between
MMP-9 and TGF-β1 expression could not be veried in
patient-derived tissue homogenates [157].
Reactive oxygen species (ROS) play a substantial role in
the immunochemistry of the cholesteatoma. ROS are known
to be related to chronic inammation and immune response
[reviewed in [158]]. Their functions comprise direct antimicrobial activity against bacteria and parasites as well as
redox-regulation of immune signaling and induction of
inammasome activation. In chronic inammation, high
doses and/or inadequate removal of ROSs result in oxidative
stress, which may damage to biological macromolecules and
results in the release of DAMPs, one of the basics roots of
cholesteatoma pathogenesis [22]. In addition to this, oxidative stress directly activates NF-κB further aggravating the
inammatory state in cholesteatoma reviewed in [159].
Studies investigating the oxidative status in cholesteatomas demonstrated that a high level of oxidation is present in
cholesteatoma. For example the general oxidative stress and
antioxidant enzyme imbalance was more severe in cases of
chronic otitis media with cholesteatoma compared to the
non-cholesteatoma groups [160]. Studies focusing on specic components of the ROS system found, that myeloperoxidase (MPO) was more intense and more often present in
cholesteatoma patients compared to chronic otitis medium
cases [161]. Usually MPO generates hypochlorite by oxidizing chlorite, which will kill bacteria and other pathogens.
However, excessive presents of this hypochlorite may also
cause oxidative damage in host tissue further accelerating
DAMP induced inammation. In addition to that the osteolysis might be directly enhanced by oxygen-derived free radicals, which act as intermediaries in the formation and
activation of osteoclasts invivo [162]. Beyond this upregulation of oxidative enzymes, the depletion of enzymatic antioxidants (e.g., superoxide dismutase, catalase, and
glutathione peroxidase) was observed in cholesteatoma
[163]. However, a relationship between activity of enzymatic
antioxidants and the extent of bone erosion was not found.
Indirect Immunoregulatory Molecules
Additional to the described inammatory regulators, many
molecules exist, which are able to indirectly modulate the
immunochemistry in the cholesteatoma niche. Since the
inltration with immunoregulatory hematopoietic cell, a
major event in the establishment of the inammatory niche
of cholesteatoma disease, the inducer of this process was
investigated in deeper detail. In general, the attraction and
differentiation of these cells are mediated by the cytokines
and chemokines expressed through the mechanisms
explained above. The transendothelial migration of the
T-cell, abundantly found in cholesteatoma tissue, is mainly
induced via the intracellular adhesion molecule- 1 (ICAM-1)
expressed on the endothelium of cholesteatoma tissue. An
enhanced expression of ICAM-1 was detected in vessels of
acquired cholesteatoma compared to normal skin [164], normal external ear canal skin, normal tympanic membrane,
normal facial ski, [165], or congenital cholesteatoma [101].
Further studies demonstrated a correlation between the
inammatory states, namely, the expression of TNF-α and
the upregulation of ICAM-1 [101]. The molecule lymphocyte function-associated antigen 1 (LFA-1) is known as a
ligand of ICAM-1 and plays a key role in the process by
which T-cells leave the bloodstream to enter the tissues.
Studies found that LFA-1 numerous LFA-1-positive cells
could be detected in the stroma of inamed acquired cholesteatomas [165] and that their number was signicantly
upregulated compared to uninamed congenital cholesteatoma [101]. Hence, another vicious cycle of self-enhancing
inammation might be present in cholesteatoma, in which
the enhanced recruitment of T-cells into the tissue leads to an
increase in inammation, upregulation of ICAM-1, and
resulting in even more T-cell migration into the cholesteatoma stroma.
T-cells play a key role in the progression of inammation
in cholesteatoma disease, the role of Human Leukocyte
Antigen – DR isotype (HLA-DR) was also more closely
investigated in the context of the cholesteatoma disease. In
general, HLA-DR functions as MHC class II cell surface
receptor presenting, e.g., bacterial antigens to T-cells.
HLA-DR is upregulated in cholesteatoma tissue [11, 166]
and abundantly expressed in macrophages present in the
perimatrix of cholesteatoma tissue [61]. In case of Langerhans
cells residing in the cholesteatoma epithelium, the expression could be detected [166, 167] but was not signicantly
upregulated [168]. This emphasize once more the inferior
role that Langerhans cell play in the immunochemistry of
cholesteatoma disease. Anyhow the high expression of
HLA-DR on macrophages in combination with the abundancy of, e.g., bacterial antigens results in the activation of
the frequently found T-cells and is thought to be the source of
the immunologically activated state of the inltrating cells
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observed in cholesteatoma tissue [169]. Macrophage and T
lymphocytes are the most frequent form all blood cells in
cholesteatoma tissue. It can be assumed that the antigen presentation of macrophages to T lymphocytes is the most frequent immune regulatory event in cholesteatoma tissue.
Genetics ofCholesteatoma
There are reports of familial clustering of cholesteatoma suggesting a genetic predisposition [170], but to date no genetic
susceptibility loci have been clearly identied [171]. A rst
systematic review about the genetics of cholesteatoma has
found a small body of evidence of a heritable component for
its etiology [172].
Investigations regarding the DNA content demonstrated
that in only one out of 10 cholesteatoma specimen, an
abnormal aneuploid DNA content was found, whereas all
six postauricular skin specimens had a normal euploid DNA
content [172]. A more recent study comprising a greater
cohort detected normal euploid DNA content on all investigated 54 specimens [173]. Two studies, aiming on the evaluating of the copy number alterations of chromosomes 3, 7,
8, and 17, found that different degrees of aneusomy were
found for all chromosomes except for chromosome 3. They
also were able to associate this copy number alterations with
the elevated proliferative rate and the aggressiveness of the
lesion [174]. When examined the telomeres of cholesteatoma tissue, their length was shorter in congenital cholesteatoma compared to normal external ear canal skin from the
same patient. But for acquired cholesteatoma, their telomere
length was almost the same as in the corresponding normal
external ear canal skin [175].
On the levels of the genetic code, few linkages between
acquired cholesteatoma and genetic alteration were identied (Fig.43.4). A polymorphisms in TLR2(Arg753Gln) was
signicantly higher in patients with chronic otitis media and
different types of mucosal changes in patients with chronic
otitis media were correlated to this polymorphism [176].
Also mutations in the CARD8 gene, which do result in an
activation of NF-κB in the context of inammation, were
investigated. It was proven that cholesteatoma patients had a
twofold and signicantly higher incidence of this CARD8
homozygous TT polymorphism. Unfortunately, cholesteatoma patients with this homozygous polymorphism suffered
under a greater bone erosion [177]. Genetic investigations in
the context of cytokines in cholesteatoma disease showed
that the 86bp variable number tandem repeat VNTR polymorphism in the IL-1RA gene was altered. The IL-1RA
allele frequency distribution was signicantly lower in cholesteatoma and led to an increased odds ratio for patients to
develop cholesteatoma [178]. In another study, the exome of
affected and unaffected individuals in families affected by
cholesteatoma was sequenced to identify variants in coding
DNA that co-segregate with the phenotype [179]. Two of the
variants identied were predicted to have a high functional
impact, both are rare, loss-of -function variants. A premature
stop codon was identied in EGFL8, and a frameshift mutation was identied in BTNL9. Additional nonsynonymous
(amino acid changing) missense mutations have been identied. But so far, this mutation could not functionally linked to
inammation and/or pathogenesis of cholesteatoma.
Another cause of the inammatory dysregulation present
in cholesteatoma tissue might lay in epigenetic alterations.
It can be assumed that the tissue memory effect in cholesteatoma cells, in regards to their inammatory response,
reects an epigenetic adaptation of the cells to the chronic
inammation present in the cholesteatoma niche. It is known
that acetylation of histone H3 at the promoters of multiple
cytokines and chemokines subsequent to initial inammation results in the increased recruitment of NF-κB to these
regions in a self-enforced positive feedback loop [180]. By
Fig. 43.4 The various
aspects of the genetics in a
cholesteatoma cell. Inside the
schemed nucleus (orange) are
the alteration on the DNA
level and their relation to
cholesteatoma disease. In the
cytoplasm (beige) are the
deregulated oncogenes and
their inuence on keratinocyte
proliferation and apoptosis
depicted
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similar means, NF-κB mediates the activation of histone H3
and H4 acetylation reviewed in [181] by DAMPs or PAMPs
is able to increase the expression of, e.g., GM-CSF [182]
observed in cholesteatoma tissue. Additionally, para- and
autocrine mechanisms in cholesteatoma tissue via IL-1β
might led to epigenetic changes in cholesteatoma cells as
well. This can be caused by the fact IL-1β is able to drive the
rapid acetylation of histones via CBP/p300, which is known
to acetylate the histones at the promoter of IL-8 [183].
Indeed, the epidermal stem cells present in cholesteatoma
tissue represent a good storage medium for epigenetic memories, since they hand their inammatory memory down to
their offspring during the repopulation of the cholesteatoma.
Similar mechanisms were already observed for other inammatory diseases and epidermal stem cells of the skin,
respectively [184].
Oncogenes also might play a role in the pathogenesis of
cholesteatoma, since they are known to cause survival and
proliferation in cells normally designated for apoptosis
(Fig.43.4). The expression of p53, famous for its role in progression through the cell cycle, was found to be 9–20 times
higher in cholesteatoma than in normal post auricular skin or
tympanic membrane [185]. Further studies showed that the
p53 protein was not only overexpressed in cholesteatoma tissue but also localized in the nucleus of keratinocytes in the
granular layer of cholesteatoma epithelium, where it further
enhances their proliferation [86]. In the same study, a likewise upregulation of c-jun, an oncogenic transcription factor,
was proven for cholesteatoma tissue. Similar to p53 the c-jun
protein was mainly localized in keratinocytes of the basal
and spinous layers of the epithelium. Another oncogene
c-myc, known for being linked to the control of growth and
differentiation, is upregulated in cholesteatoma compared to
atheroma and to normal skin [186]. Hence, it is also subjected to play a role in the pathogenesis of cholesteatoma
disease. Investigations utilizing in situ hybridization found
that 10 out of 15 cholesteatoma cases showed enhanced frequency of c-myc and likewise to [174] aneuploidy of chromosome 8, the chromosome to which the c-myc gene is
localized [187]. They concluded that the deregulating c-myc
expression in cholesteatoma might be related to the enhanced
c-myc copy number. Another study focused on the localization of c-myc and detected the protein in the nucleus of cholesteatoma epithelium, where it is able to effectively enhance
the expression of various genes related to epithelial proliferation. In contrast to that, it was only in an inactive state and
localized in the cytoplasmatic region in normal skin [188].
The tumor suppressor p27 was signicantly downregulated
vefold in cholesteatoma tissue [189]. Since alterations of
p27 levels in keratinocytes can inuence their proliferative
state, the investigators suggested that the altered p27 levels
in cholesteatoma may contribute to the pathology in cholesteatoma. Another study was able to detect an enhance expres-
sion of p63, belonging to the p53 gene family, in
cholesteatoma tissue [190]. Since p63 is involved in multiple
functions during skin growth and development, they concluded that this nding might be linked to the excessive epithelial cell growth characteristic for middle ear cholesteatoma.
The tumorsupressor PTEN and PDCD4 were found to be
greatly reduced in 3 of 4 cholesteatoma samples. This could
be linked to their regulatory miRNA-21, which was upregulated 4.4 fold in cholesteatoma [191]. In accordance with
that, another study detected that let-7a downregulates the
expression of miRNA-21 and that this mechanism resulted in
the suppression of proliferation and induction of apoptosis in
keratinocytes derived from cholesteatoma presumably
through PTEN and/or PDCD4 [192]. Additional studies
could link the expression of PTEN to miRNA-802 [193].
They found a direct link between the enhanced NF-κB signaling, miRNA-802 expression, miR-802 induced repression
of PTEN, and the promotion of keratinocyte cell proliferation. They concluded that the NF-κB/miR-802/PTEN signaling pathway plays an important role in the development of
cholesteatoma.
Discussion
This chapter of the book illustrates the complex and multilayered immunoregulatory network of cholesteatoma disease. Similar to many chronical inammations, the chronic
form of otitis media is able to severely change the nely
tuned immunochemical interplay initially designed to protect our body. We described how long-term exposure of the
middle ear to tissue damage (DAMPs) and infections
(PAMPs) can overload its innate immune system and cause
long time tissue stress, which results in an exaggerated
immune reaction in the middle ear.
We described numerous predispositions making the
immune system of some chronic otitis media patients go out
of course. It might start with an upregulation of some PRRs,
which can result in an oversensitive response to the present
DAMPs and PAMPs. This results in an increase inammatory output of the cells present in the middle ear. Subsequently,
much too many immune cells, mainly mast cells macrophages and T-cells, are recruited to the side. These cells are
potent immune regulators and further raise the level of various immunoregulatory extracellular signals resulting in an
additional tightening of the highly inammatory state of
cholesteatoma. This mechanism, which can already be
described as vicious circle, can be intensied by cholesteatoma characteristics. On one hand, the acceleration of proliferation and cell death in the matrix generates more and more
DAMPs, and on the other hand, the high concentrations of
PRRs like RAGE and TLR-4 are able to further enhance the
DAMP driven output. Furthermore, positive feedback loops
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do exist in the middle ear under this condition of heavy
chronic inammation. They are capable to tip the equilibrium of the immunochemistry of cholesteatoma tissue even
more out of balance. The most prominent are the self-induced
expression of cytokine like TNF-α highly expressed in cholesteatoma tissue, the self-enhancing interplay between
IL-1β and GM-CSF in the keratinocytes/broblast network,
or the NF-κB driven acetylation of histones driving cytokine
expression paracrinely enabling further NF-κB activation. In
the end of this disturbed tissue homeostasis, an exaggerated
expression of paracrine signaling related to the wound healing process is able to further boost the proliferation of epidermal cells, the most prominent symptom of cholesteatoma
development and osteoclast maturation and activation and
subsequent bone erosion. Hence, this highlights mechanisms, designed to protect the middle ear in the case of the
otitis media, are able to turn from a protector into an aggressor during prolonged inammation and the concomitant tissue stress.
Conclusions andFuture Work
The only medical treatment of cholesteatoma is a surgical
intervention. It is known that the probability of cholesteatoma recurrence is highly depended on the radicalism of the
surgical treatment [194]. Besides this, the recurrence is often
correlated to the high level of inammation [195]. Therefore,
a reduction in the inammatory burden is most favorable for
the postsurgical therapy.
As described, one source of this inammation is PAMPs.
Hence, postsurgical application of antibiotics is commonly
utilized to reduce the abundancy of PAMPs. Unfortunately,
the infection of cholesteatoma tissue is most often present in
the form of a biolm [29, 196, 197]. Hence, the applied antibiotics do not completely eradicate the infection and are only
able to reduce the bacterial load for a short time. The release
of DAMPs from the inamed and decomposing tissue always
goes along with cholesteatoma disease and thus is hard to
prevented. Anyhow, a specic approach might be the selective inhibition of COX-2, which is upregulated in cholesteatoma tissue, by nonsteroidal anti-inammatory drugs. This
will reduce the synthesis of the DAMP PEG and hence
reduce the inammatory state. A more direct approach would
be to aim on the main gate to inammatory signaling inside
cholesteatoma tissue, the PRRs. Clinical relevance of RAGE
inhibition in inammatory disease is being demonstrated in
emerging clinical trials investigating novel small-molecule
RAGE inhibitors [198]. The TLR4, probably the major driver
of the exaggerated cholesteatoma inammation, might be
blocked by antagonists, which were clinically investigated
already like Eritoran [199] or TAK-242 [200]. We think that
the postsurgical topical application of these noncytotoxic
substances might signicantly decrease cholesteatoma recurrence. Downstream of PRRs lays the multilayered inammatory landscape. Its high level of inammation exacerbated
itself through numerous positive feedback loops. Because of
the diversity of targets found on the level of extracellular signaling, a therapy based on molecular strategies seems unfavorable. Thus, anti-inammatory drug with broad spectrum
was investigated. The popular drug dexamethasone showed
good results in invitro models [146]. In clinical trials, the
topical application of dexamethasone postsurgery was also
able to perform well and reduced the recurrence rate.
Unfortunately, long-term application of these substances is
not possible, since it will lead to infections of the middle ear.
But topical treatment of the operation side with steroids
directly after surgery is common in cholesteatoma surgery to
reduce the inammation at least for a short period of time. At
the end of the inammatory cascade described in this chapter
arise the symptoms of cholesteatoma disease, amely, hyperproliferation of epidermal cells and bone resorption. In the
past, different approaches were made to induce apoptosis in
epidermal cells by heavy cytotoxic drugs usually applied on
cancer patients [201, 202]. But the activated oncogenes
described above, who drive the proliferation of cholesteatoma epidermal cells, might offer a target for more sophisticated molecular-based treatment strategies, which are
applied nowadays in up to date cancer research.
We hope that this chapter will help the readers to gain a
better insight into cholesteatoma pathogenesis, the primary
root of the progression, and recurrence of cholesteatoma disease. A profound understanding of the links between inammation, wrongly coined innate immune system, and
extracellular signaling is needed. This may lead to novel
pharmaceutical strategies enable to interrupt these pathways.
Eventually, it would improve cholesteatoma treatment, thus
enabling the preservation of middle ear function for many
cholesteatoma patients.
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