Toll-like Receptor 2 Activation and Comedogenesis in Acne
Toll-like Receptor 2 Activation and Comedogenesis in Acne
Acne is characterized by the formation of comedones, but the etiology of these lesions remains unclear, although cutaneous pathogens are most likely involved. High levels of the pro-inflammatory cytokine IL-1α were reported in acne lesions in vivo, and previous work revealed that exposure of isolated infundibula and pilosebaceous units to IL-1α in vitro induced comedone formation. Because comedone formation reflects the development of infundibular epidermal scaling, this finding is important because it suggests that IL-1α, whose role in the epidermis remains to be fully elucidated, is a mediator of scaling in inflammatory skin disease. We sought to establish a link between cutaneous flora, the release of IL-1α and the acne life-cycle.
The epidermis provides the first line of defense against invasion by pathogens. Whilst the epidermis contains antigen-presenting Langerhans cells of the adaptive immune system, keratinocytes also 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. The activation of the prototypical innate Drosophila receptor Toll is central to this innate response, leading to the release of antifungal factors. A related family of Toll-like receptors (TLRs) are widely expressed in mammalian tissues, particularly epithelia, and growing body of research indicates the importance of innate immunity in cutaneous pathology. Eleven mammalian Toll homologues have been characterised to date, each recognizing a discrete set of invariant moieties associated with infectious agents called pathogen associated molecular patterns, or PAMPs. Notable PAMPs include peptidoglycan (PGN) a component of the coats of gram-positive bacteria (including P. acnes), lipopolysaccharide (LPS) from gram-negative bacteria, or unmethylated CpG DNA characteristic of viruses, which activate TLR2, TLR4 and TLR9 respectively [reviewed in. 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 (β-defensins and reactive oxygen species) and cytokines (including IL-1α) via an NFκB-dependent mechanism.
There is much speculation regarding the source of infundibular IL-1α in acne, and there are reports of release either by keratinocytes or by the cells of the immune system. Since IL-1α release is a consequence of TLR signaling in many cell types including keratinocytes, we wished to investigated if the exposure of sebaceous glands maintained ex vivo to PAMPs induced hypercornification via the TLR-stimulated release of IL-1α.
Background
Acne is characterized by the formation of comedones, but the etiology of these lesions remains unclear, although cutaneous pathogens are most likely involved. High levels of the pro-inflammatory cytokine IL-1α were reported in acne lesions in vivo, and previous work revealed that exposure of isolated infundibula and pilosebaceous units to IL-1α in vitro induced comedone formation. Because comedone formation reflects the development of infundibular epidermal scaling, this finding is important because it suggests that IL-1α, whose role in the epidermis remains to be fully elucidated, is a mediator of scaling in inflammatory skin disease. We sought to establish a link between cutaneous flora, the release of IL-1α and the acne life-cycle.
The epidermis provides the first line of defense against invasion by pathogens. Whilst the epidermis contains antigen-presenting Langerhans cells of the adaptive immune system, keratinocytes also 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. The activation of the prototypical innate Drosophila receptor Toll is central to this innate response, leading to the release of antifungal factors. A related family of Toll-like receptors (TLRs) are widely expressed in mammalian tissues, particularly epithelia, and growing body of research indicates the importance of innate immunity in cutaneous pathology. Eleven mammalian Toll homologues have been characterised to date, each recognizing a discrete set of invariant moieties associated with infectious agents called pathogen associated molecular patterns, or PAMPs. Notable PAMPs include peptidoglycan (PGN) a component of the coats of gram-positive bacteria (including P. acnes), lipopolysaccharide (LPS) from gram-negative bacteria, or unmethylated CpG DNA characteristic of viruses, which activate TLR2, TLR4 and TLR9 respectively [reviewed in. 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 (β-defensins and reactive oxygen species) and cytokines (including IL-1α) via an NFκB-dependent mechanism.
There is much speculation regarding the source of infundibular IL-1α in acne, and there are reports of release either by keratinocytes or by the cells of the immune system. Since IL-1α release is a consequence of TLR signaling in many cell types including keratinocytes, we wished to investigated if the exposure of sebaceous glands maintained ex vivo to PAMPs induced hypercornification via the TLR-stimulated release of IL-1α.