Abstract
BackgroundAcne is a common disorder of the human pilosebaceous unit, yet the mechanisms underlying hyperkeratinisation and subsequent inflammation (comedogenesis) remain to be determined, although cutaneous pathogens are implicated. Previously, it was reported that the release of the cytokine interleukin-1α (IL-1α) by keratinocytes of the sebaceous duct was pivotal in the life cycle of the comedone, mediating both its development and its spontaneous resolution. Toll-like receptors are a family of molecules that recognise pathogen associated molecular patterns (PAMPs) presented by microorganisms, initiating a signalling cascade terminating in the release of antimicrobial compounds and cytokines.MethodsWe used ex vivo sebaceous gland and primary monolayer keratinocyte culture, alongside ELISAs, immunohistochemistry, Western blotting and RT-PCR to investigate the contribution of TLR activation to acne pathogenesis.ResultsWe found TLR2 to be expressed in basal and infundibular keratinocytes, and sebaceous glands, and its activation provoked the release of IL-1α from primary human keratinocytes in vitro. The exposure of microdissected human sebaceous glands to PAMPs specific for TLR2 in vitro resulted in a pattern of IL-1α like cornification after seven days of exposure.ConclusionsTLR activation and secretion of IL-1α from keratinocytes may be initiating steps in comedogenesis and, therefore, critical to the pathophysiology of acne.
Highlights
Acne is a common disorder of the human pilosebaceous unit, yet the mechanisms underlying hyperkeratinisation and subsequent inflammation remain to be determined, cutaneous pathogens are implicated
Antibodies raised against human TLR2 and TLR4 were obtained from HyCult Biotechnology bv (Uden, Netherlands) and used at 100 μg/ml to block the effect of the pathogen associated molecular patterns (PAMPs)
TLR2 is expressed in human sebaceous glands and keratinocytes Expression of TLR2 mRNA in sebaceous glands from ten individuals, as well as in normal human epidermal keratinocytes (NHEK) and HaCaT keratinocytes, was profiled by PCR (Figure 1A)
Summary
Acne is a common disorder of the human pilosebaceous unit, yet the mechanisms underlying hyperkeratinisation and subsequent inflammation (comedogenesis) remain to be determined, cutaneous pathogens are implicated. Toll-like receptors are a family of molecules that recognise pathogen associated molecular patterns (PAMPs) presented by microorganisms, initiating a signalling cascade terminating in the release of antimicrobial compounds and cytokines. Whilst the epidermis contains antigen-presenting Langerhans cells of the adaptive immune system [4], keratinocytes have inherent mechanisms to combat infection This innate immunity is a remnant of an ancient host defense mechanism shared with lower organisms, pre-dating adaptive immunity. PAMPs are recognised by a leucine-rich extracellular TLR domain, initiating a signal transduction cascade via an intracellular interleukin-1 receptor (IL-1R)-like region, characteristically leading to the release of antibacterial compounds (βdefensins and reactive oxygen species) and cytokines (including IL-1α) via an NFκB-dependent mechanism [10,11]
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