Cell Tissue Res (2014) 358:697–704
DOI 10.1007/s00441-014-1999-1
MINI REVIEW
Deciphering the functions of the hair follicle infundibulum in skin
physiology and disease
Marlon R. Schneider & Ralf Paus
Received: 12 May 2014 / Accepted: 4 September 2014 / Published online: 24 September 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract The infundibulum is the funnel-shaped, uppermost
epithelial segment of the hair follicle. Thus, as the infundibu-
lum represents a major interface zone of mammalian skin
epithelium with the environment and harbors a rich residential
microflora, it is not surprising that this area is endowed with a
specialized immune system and innate immune defenses.
Clinically, the infundibulum is quite important, as it becomes
prominently involved in many skin diseases such as acne,
infundibular folliculitis and cysts, hidradenitis suppurativa,
keratosis pilaris, Fox-Fordyce disease, and a subtype of basal
cell carcinoma. Nevertheless, the biology of the infundibulum
is only poorly understood, and it remains largely unknown
how exactly the infundibulum contributes to skin disease, and
how it might be targeted effectively for treating important skin
diseases. Several recent studies in mouse models have identi-
fied new potential infundibular markers, shed light upon in-
fundibular development and homeostasis, identified infundib-
ular epithelial stem cells, and have implicated the infundibu-
lum in the pathogenesis of additional skin disorders. These
recent insights encourage one to systematically re-visit the
biology and pathology of the infundibulum, one of the most
important, yet least-studied frontiers in mammalian epithelial
physiology.
M. R. Schneider (*)
Institute of Molecular Animal Breeding and Biotechnology Gene
Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich,
Germany
e-mail: marlon.schneider@lmu.de
R. Paus
Dermatology Research Centre, Institute of Inflammation and Repair,
University of Manchester, Manchester M13 9PT, UK
R. Paus
Laboratory for Hair Research and Regenerative Medicine,
Departments of Dermatology, University of Münster,
D-48149 Münster, Germany
Keywords Skin . Hair follicle . Infundibulum
Hairs, a fundamental characteristic of mammals, are produced
by hair follicles (HF), epidermal appendages that display
continuous cycles of growth (anagen), apoptosis-driven re-
gression (catagen), and relative rest (telogen) (Schneider et al.
2009). The HF is usually divided in a relatively permanent
upper part, which morphologically does not appear to undergo
much changes during HF cycling but may be less permanent
than often assumed (Lindner et al. 1997; Geyfman et al.
2012), and a lower part that is extensively remodeled during
each HF cycle (Fig. 1). The lower, proximal part of the HF is
formed by the hair bulb, the actual hair shaft factory, and the
suprabulbar region, whose maximal length is attained during
anagen. The HF’s upper, distal part can be separated into four
compartments. The bulge region of the outer root sheath
(ORS), the seat of HF epithelial stem cells (Purba et al.
2014), the isthmus and the junctional zone (the regions below
or around the insertion of the sebaceous gland duct, respec-
tively), and the infundibulum, which extends from the en-
trance of the sebaceous duct to the HF ostium, the opening
of the HF onto the skin surface (Fig. 1).
In human terminal HF, the infundibulum has an average
length of 0.6–0.8 mm, accounting for 15–20 % of the total HF
length (Vogt et al. 2007; Jimenez et al. 2011). Compared to the
bulge, the skin’s major reservoir of epithelial and melanocyte
stem cells, and to the bulb, the HF’s busy hair shaft factory, the
infundibulum displays a rather unpretentious arrangement,
and appears to be routinely disregarded as a simple canal that
endures and, perhaps, somehow guides the repeated outwards
passages of a hair shaft.
This, however, is a misconception, as the infundibular
epithelium is far more actively involved in HF biology and
pathology than is widely appreciated. Moreover, it harbors a
rich residential microflora, whose exact composition, role in
698
Fig. 1 Schematic representation of a mouse hair follicle at the anagen or
telogen stage of the hair cycle. The term “isthmus” tends to be used
inconsistently by different authors. We use this term to indicate the region
skin physiology and interaction with the skin immune system
is only slowly becoming unraveled. In both mice and human
HFs, the infundibulum is a major site of chemokine produc-
tion (Nagao et al. 2012), a rich source of various antimicrobial
peptides (Reithmayer et al. 2009; Emelianov et al. 2012), and
prominently expresses toll-like receptors (Selleri et al. 2007;
Reithmayer et al. 2009). In contrast to the MHC class I-
negative bulge and the epithelium of the anagen hair bulb
(Meyer et al. 2008; Paus et al. 2005), the infundibulum is
everything but immunoprivileged. Instead, it displays a fully
functional antigen recognition and presentation system that
includes MHC class I+ (and thus autoantigen-, viral- and
tumor antigen-presenting) ORS keratinocytes (Paus et al.
1994a), MHC class II+ Langerhans cells, and a dense popula-
tion of gamma/delta T cells (Paus et al. 1994b; Bertolini et al.
2013; Kloepper et al. 2013).
It has been speculated that this complex antigen recogni-
tion and response system, which is complemented by
perifollicular macrophages and mast cells in the HF’s imme-
diately adjacent mesenchyme, the connective tissue sheath
(CTS) (Paus et al. 1998; Christoph et al. 2000) (Fig. 1), may
be instrumental in educating the immune system to launch
differential responses to the HF’s rich residential microflora
Cell Tissue Res (2014) 358:697–704
of the ORS that is located above the bulge and immediately below the
junctional zone, i.e. the area around the insertion of the sebaceous gland
duct into the ORS
that is in contact with the distal HF epithelium, including at
least parts of the infundibulum; these differential responses
would include tolerance to the rich residential microflora
while retaining the capacity to launch both rapid innate and
acquired immune response against pathogens that enter the
body via the transfollicular route (Paus et al. 2005). Thus, the
IF’s capacity to secrete chemokines and AMPs in a hair cycle-
dependent manner (Reithmayer et al. 2009; Emelianov et al.
2012; Nagao et al. 2012), to thereby direct Langerhans cell
trafficking (Nagao et al. 2012), and to remodel its
intraepithelial Langerhans cell and gamma/delta T cell popu-
lations (Paus et al. 1994b, 1998; Kloepper et al. 2013) may
play a more important role in modulating the skin immune
status and intracutaneous signaling milieu than has previously
been realized.
For decades, the only circumstances conferring the infun-
dibulum some glamour were the awareness that the size and
shape of the infundibulum are important determinants of drug
penetration, and the fact that infundibular hyperkeratosis is a
key element in the pathogenesis of both acne vulgaris and
hidradenitis suppurativa/acne inversa (see below). Clinically,
the infundibulum is also appreciated for its involvement in the
pathogenesis of keratosis pilaris, infundibular folliculitis and
Cell Tissue Res (2014) 358:697–704 699

cysts, hidradenitis suppurativa, Fox-Fordyce disease, and a cornification proteins, potentially contributing to the forma-
subtype of basal cell carcinoma, infundibular BCC (Weedon tion of the HF orifice. This study also suggests a role for
2010; McKee 2012). migrating, K79+ keratinocytes during hair regeneration in
It is therefore rather surprising that, so far, only a few adult HF (Veniaminova et al. 2013). While this report is
studies have focused on the infundibulum. Concentrating on promising, some issues must be resolved before K79 can be
the HF infundibulum of mice, the current review exposes the widely employed as an infundibular marker. As Veniaminova
“Cinderella” status of the infundibulum and sketches impor- and colleagues employed a GLI2 antibody that cross-reacts
tant areas for future research on this neglected compartment of with K79 to detect the latter protein, it would be important to
the distal HF epithelium. We examine recent progresses in confirm the shown K79 expression pattern in the skin by in
understanding the development and homeostasis of the infun- situ hybridization and by employing additional, ideally com-
dibulum and assess the evidence implying this structure in the mercially available antibodies. Furthermore, K79 expression
pathogenesis of numerous skin disorders. We propose that in epithelia other than skin, such as that of the gastrointestinal
these and future advances will deepen our understanding of tract, should be evaluated. Finally, as mouse and human
HF biology and invite novel strategies for treating selected epidermis and HFs differ considerably regarding important
common skin diseases. anatomical and functional aspects (Schneider 2012), the in-
fundibular expression of K79 should be demonstrated in
human tissues as well to be of general relevance.
Recent advances in research on infundibulum To identify the stem cells that give rise to the infundibulum
development and homeostasis during homeostasis, Veniaminova et al. (2013) focused on
LRIG1, a transmembrane protein enriched in stem cells in
HF development in mice initiates at E14.5, and a hair canal the junctional zone that were previously shown to contribute
becomes visible for the first time at the stage 6 of follicle to the infundibulum, the interfollicular epidermis, and the
morphogenesis, when primitive IRS cells migrate to the top of sebaceous gland (Jensen et al. 2009). In a classic lineage-
the developing follicle (Paus et al. 1999). The study of infun-
dibulum morphogenesis has been largely precluded by the
scarcity of reliable markers. Until now, proposed infundibular
markers included small proline rich protein 1 (Sprr1)
(Fujimoto et al. 1997) and keratin 17 (Kurokawa et al. 2002)
for human skin, and Sprr1 (Owens et al. 1996), K17
(Panteleyev et al. 1997), cystatin 6 (Zeeuwen et al. 2002),
and stem cell antigen 1 (Jensen et al. 2008) for mouse skin.
Although frequently referred to as infundibular “markers”,
these proteins are also expressed at additional sites of the HF
or interfollicular epidermis.
Recently, Veniaminova et al. (2013) confirmed the expres-
sion of the above markers in the mouse infundibulum and
identified keratin 79 (K79) as a new putative infundibular
marker. K79 has been previously put forward as a sweat gland
marker, but the authors failed to assess its expression in
epithelia others than mouse foot pads (Kunisada et al. 2009).
By staining mouse embryonic skin with an antibody
(Ag-7195) developed against GLI2 that recognizes K79,
Veniaminova and colleagues showed that K79 marks cells
along the entire suprabasal layer of the infundibulum and
sebaceous glands in telogen HFs (Fig. 2a). After confirming
that Ag-7195 reveals K79 localization, the authors could show
that the specification of cells lining the future HF canal occurs
significantly earlier than it was previously believed. More Fig. 2 a Immunofluorescence against Ag-7195 (reflecting K79 localiza-
importantly, their findings suggest a novel mechanism for tion) in a standard histological section (left) or an epidermal whole mount
lumen formation during HF morphogenesis. According to this (right). b β-galactosidase staining of skin from Lrig1-CreERT2/ROSA26-
lacZ mice at the indicated time points after tamoxifen-induced expression
model, K79+ cells initially migrate outwards, extending from of the reporter. Images are republished with permission of the Company
the hair germ into the epidermis; subsequently, distal cells of of Biologists, from Veniaminova et al. (2013); permission conveyed
the K79+ stream start expressing proteolytic enzymes and through the Copyright Clearance Center
700
tracing approach employing tamoxifen-inducible Lrig1-
CreERT2 mice and appropriate reporter lines, Veniaminova
and colleagues showed that following activation of
Lrig1-directed cre expression, the infundibulum is pro-
gressively filled with reporter-marked cells (Fig. 2b). In
doing so, the latter authors demonstrated that the infun-
dibulum (and to a lesser extent the sebaceous gland) is
maintained by LRIG1+ cells, confirming a more recent
report from the K. B. Jensen group (Page et al. 2013).
Together, these data convincingly show that the infun-
dibulum in murine HFs is normally replenished by the
upward movement of LRIG1+ stem cells located in the
HF junctional zone.
The infundibulum in human skin diseases
Acne vulgaris
The pathogenesis of acne vulgaris can be summarized in the
following elements: increased sebum production, abnormal
desquamation of the HF canal lining cells, leading to the
formation of a comedo, and increased microbial colonization
(in particular by P. acnes) and inflammation of the follicle
(Kurokawa et al. 2009; Well 2013). Acne vulgaris develops
exclusively in sebaceous follicles, one of the three HF types
found in human facial skin and characterized by exceptionally
large sebaceous glands and wide, tortuous canals. Although a
few animal models of acne are available, such as the Mexican
hairless dog, the rhino mouse, and the rabbit ear assay
(Mirshahpanah and Maibach 2007), it is primarily the absence
of comparable HF in other animals that explains why acne
reputedly occurs in human beings only.
The earliest pathological change during acne development,
the formation of a microcomedo and blockage of the follicular
canal, is strongly related to the peculiar features of the seba-
ceous follicle infundibulum. Its upper portion, occasionally
called acroinfundibulum, strongly remembers the adjacent
epidermis, with which it shares a similar keratinization pattern
(Plewig and Kligman 2000). The lowest part, the
infrainfundibulum, shows a less robust structure and its kera-
tinization results in a fragile horny layer whose cells soon
slough, resulting in the accumulation of a loose mass of cell
debris in the canal (Knutson 1974). There is also evidence for
functional differences between both compartments, such as
increased capacity of androgen synthesis in infrainfundibular
keratinocytes (Thiboutot et al. 1997).
Acne initiation, accordingly, has been associated with a
number of pathologic features affecting the infrainfundibulum,
including increased proliferation of its lining keratinocytes,
enhanced or abnormal keratinization, and increased corneocyte
cohesiveness (Plewig et al. 1971; Knutson 1974; Hughes et al.
1996; Kurokawa et al. 1988). Next, increased sebum and
Cell Tissue Res (2014) 358:697–704
keratin accumulation results in the formation of a comedo, that
may remain closed or dilate the follicle to form an open
comedo. Ultimately, the traction forces generated by the
comedo trigger the inflammatory lesions of acne.
Another interesting finding recently reported by
Veniaminova et al. (2013) was the fact that the newly identi-
fied infundibular marker K79 was lost in five of seven closed
comedones removed from the face of acne patients. While
these findings suggest that K79 might be lost during the
progression of acne, the authors reported unchanged K79
expression in the dermal cysts observed in a mouse model
with impaired Notch signalling. Yet, to what extent are the
cysts observed in mice with genetic ablation or expression of
dominant-negative Notch pathway components adequate
models for comedogenesis?
Similar, sometimes keratin-filled cysts, have been reported
in the dermis of mouse lines with functional alterations in a
large number of additional proteins and pathways, including
the retinoid X receptor alpha (Li et al. 2000), the vitamin D
receptor (Keisala et al. 2009), phospholipase C (Nakamura
et al. 2003), Rac1 (Benitah et al. 2005), ADAM10 (Weber
et al. 2011), and the Wnt pathway, among others (reviewed in
Nakamura et al. 2013). However, such lesions are quite dis-
tinct from the changes observed in human sebaceous follicles
during early acne stages. The skin lesions in mice with the
highest similarities to acne are utricles, HF expansions con-
taining keratinized debris located adjacent to the sebaceous
gland, described so far in only very few mouse lines, such as
those carrying mutations in the hairless gene (Panteleyev et al.
1998; Zarach et al. 2004) or deficient for cathepsin L (Tobin
et al. 2002; Potts et al. 2004).
Chloracne/MADISH
A recent report provides more details about the pathogenesis
of utricle-like infundibular changes in transgenic mice with
skin abnormalities resembling metabolizing acquired dioxin-
induced skin hamartomas (MADISH, also known as chlorac-
ne), a human disease characterized by severe acne-like skin
eruptions that became widely known through the dioxin poi-
soning of the former Ukrainian president, Victor Yushchenko
(Saurat et al. 2012).
Specifically, long-term overexpression of the transcription
factor Nrf2, a key regulator of the cellular stress response, was
shown to result in infundibular acanthosis and hyperkeratosis,
resulting in a widened infundibulum with accumulation of
sebum and keratin, which is further aggravated by enlarged
sebaceous glands (Schafer et al. 2014). Mechanistically, the
authors identified three Nrf2 target genes that seem to con-
tribute to the disease at different ratios. The primary reason for
the infundibular acanthosis and the increased sebum produc-
tion can be traced back to the upregulation of epigen, a ligand
of the epidermal growth factor receptor (EGFR) (Schneider
Cell Tissue Res (2014) 358:697–704
and Yarden 2013). Interestingly, overexpression of epigen in
transgenic mice was previously shown to result in se-
baceous gland enlargement (Dahlhoff et al. 2010, 2014).
Pharmacological blockade of EGFR signaling rescued
the sebaceous gland hyperplasia and the
hyperproliferation of infundibular keratinocytes in Nrf2
transgenic mice (Schafer et al. 2014). The other two
upregulated Nrf2 target genes involved are Slpi (secre-
tory leukocyte peptidase inhibitor), encoding a protease
required for corneodesmosome cleavage, and Sprr2d
(small proline rich protein 2d), encoding a protein of
the cornified envelope. Increased levels of Slpi may be
responsible for the infundibular hyperkeratosis, while
Sprr2d upregulation may be another causal component
of infundibular acanthosis by reducing barrier function-
ality (Schafer et al. 2014).
Notably, in aged (∼1-year-old) Nrf2 transgenic mice, the
continuous infundibular hyperkeratinization leads to a pro-
gressive dilatation of this structure and to the formation of
keratinized cysts (Schafer et al. 2014). As the larger cysts
either lack sebaceous glands or are associated with very small
glands, these skin lesions fulfill the major histological criteria
for being classified as a MADISH-like disease. Finally,
Schäfer et al. (2014) detected strong expression of EPGN,
SPRR2, and SLPI in the epidermis and cyst epithelium of
MADISH patients, thus providing strong evidence for their
contribution to the pathogenesis of cyst development in hu-
man patients.
Fig. 3 Summary of recent
advances in infundibulum
development, homeostasis, and
pathology
701
Other skin diseases
The infundibulum has been implicated in a number of skin
disorders in addition to acne and MADISH. It was identified
as a clinically relevant colonization site of pathogenic
Malassezia yeasts, and it was shown that an efficient and
selective delivery of antifungal substances to the infundibu-
lum is a pre-requisite for the successful treatment of dandruff/
seborrhoeic dermatitis (Schwartz et al. 2011). Inflammation
and damage of the infundibulum are early hallmarks of an-
drogenetic alopecia (Nirmal et al. 2013) and possibly even
alopecia areata (Zhang et al. 2013), the most frequent human
autoimmune hair loss disorder, which is conventionally con-
sidered to be restricted to the hair bulb (Gilhar et al. 2012;
McElwee et al. 2013).
In hidradenitis suppurativa, a painful and debilitating
chronic inflammatory disease also known as acne inversa,
the first histological changes are psoriatiform hyperplasia
and keratosis of the follicular infundibulum (van der Zee
et al. 2012). Interestingly, expression of K17, a keratin abun-
dantly expressed in the infundibulum and sebaceous ducts of
normal skin, was shown to be lost in the infundibular-like
epithelial lesions of hidradenitis suppurativa patients
(Kurokawa et al. 2002).
A recent study revealed that progenitor cells residing in the
upper infundibulum may contribute, even if to a less extent
than the interfollicular epidermis, to the development of
experimentally-induced basal cell carcinoma (BCC) in mice
702
(Youssef et al. 2010). Tumors of the follicular infundibulum
are relatively rare in humans (Martin et al. 2009). However,
while most human BCC cases originate from the
interfollicular epidermis, there is a BCC subtype
(infundibulocystic BCC) that shows differentiation towards
the HF infundibulum (Crowson 2006).
Concluding remarks
Translational relevance and clinical perspectives
This review highlights that the infundibulum is a functionally
important compartment of the HF epithelium that is highly
sensitive to external and internal stimuli. In particular, the
specific keratinization pattern and the associated reduction in
the number of differentiated corneocytes in its lower segment
represent a clear interruption of the skin barrier. Its naturally
increased permeability, together with an inherent susceptibil-
ity to abnormal keratinization, facilitate inflammatory pro-
cesses and can be considered an Achilles’ heel for the devel-
opment of skin diseases as acne, hidradenitis suppurativa, or
some forms of alopecia. At the same time, in accordance to its
morphological continuity to the interfollicular epidermis, the
infundibulum represents only a weak barrier to the external
milieu. For example, in situ melanomas have been shown to
easily spread through the infundibulum, being hindered in
their penetration only at the level of the bulge (Pozdnyakova
et al. 2009).
This prompts us to inquire whether pathological changes of
the infundibulum may be involved in the development of
further skin diseases such as additional forms of alopecia or
psoriasis. Support for an involvement of the infundibulum in
the latter disease comes from the observation that the
interfollicular epidermis and the infundibulum have common
progenitor cells, as they can be maintained by the same
LRIG1+ stem cell pool located at the junctional zone, at least
in mice (Veniaminova et al. 2013; Jensen et al. 2009). Further
support for a role of the infundibulum in psoriasis comes from
follicular psoriasis, a neglect disease characterized by dilated
infundibula with marked parakeratotic plugging and neutro-
phil infiltration (Arps et al. 2013).
Key models for future research
A number of proteins are already known to be differentially
regulated in the infundibulum of patients with skin diseases.
Examples include loss of keratin 17 in hidradenitis
suppurativa (Kurokawa et al. 2002), increased expression of
K6, K16 and K17 in the acne comedone wall (Hughes et al.
1996), or, more recently, loss of K79 in closed acne comedo-
nes (Veniaminova et al. 2013). As the HF infundibulum
Cell Tissue Res (2014) 358:697–704
becomes better characterized, we will probably identify a role
in infundibular biology and pathology for hitherto unappreci-
ated protein groups such as members of the Sprr family,
structural proteins that are crosslinked to become part of the
epidermal cornified envelope (Candi et al. 2005). It has long
been known that Sprr1 is strongly expressed in the HF infun-
dibulum, while SPRR3 expression, normally absent or ex-
tremely low in the epidermis and HF, is induced in hyperplas-
tic and malignant skin lesions (Fujimoto et al. 1997). In light
of the recently reported upregulation of Sprr2d and SPRR2 as
the reason for the acanthosis and reduced barrier functionality
in Nrf2 transgenic mice and for cyst formation in the skin of
MADISH patients, respectively (Schafer et al. 2014), it would
be interesting to systematically study the expression pattern of
other family members in normal skin and in samples of
patients with HF diseases.
Another potential future development is the use of
infundibulum-specific regulatory sequences (such as that of
the Krt79 gene) to direct gene expression or deletion specifi-
cally to this segment of the HF, for instance by employing the
Cre-loxP or Tet-On/Tet-Off systems (Schneider 2012). Also,
the availability of a growing number of molecular markers
may allow the isolation of infundibular primary cells or stable
cell lines, thus encouraging more precise studies of gene
expression or cytokine signalling, an important complemen-
tation to the already available system for culturing the isolated
human infundibulum (Guy and Kealey 1998). All these stud-
ies would greatly benefit from a systematic characterization of
infundibular structure and cellular composition, particularly
regarding differences between infundibular architecture in
different hair follicle types both in mice and in humans.
In conclusion, we anticipate that the recent increase in IF
research, summarized in Fig. 3, will significantly expand our
knowledge about the roles of this HF segment in skin biology
and pathology, ultimately leading to novel approaches for
treating skin diseases.
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