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Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, GermanyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, GermanyCluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
Dysfunctional autophagy is linked to various diseases, including psoriasis and atopic dermatitis. Recent evidence suggests that exposure of keratinocytes to TNF-α results in impaired autophagy and lysosomal function. The skin of patients with psoriasis and atopic dermatitis reveals a decreased expression of lysosomal cathepsins. Impaired autophagy is presumably involved in inflammation and disturbed keratinocyte differentiation, whereas stimulating autophagy might be a treatment option in inflammatory skin disease.
Autophagy is an essential biological process that involves intracellular quality control, metabolism, and cell survival and that enables cells to recycle cytoplasmic materials under stress conditions. Macroautophagy, which is the best understood form of autophagy, has been also implicated in several aspects of the immune response, including lymphocyte development, innate immunity, antigen presentation, and antigen receptor signaling (
). During autophagy, cytoplasmic material is identified by autophagy receptors, such as p62/SQSTM1, and collected in double-membrane autophagosomes. These structures subsequently fuse with lysosomes, where the cargo is degraded by acidic hydrolases, such as proteases of the cathepsin family. Owing to its fundamental role in cellular homeostasis, deregulated autophagy has been associated with various diseases, including cancer, metabolic disorders, neurodegeneration, cardiovascular and liver diseases, as well as infections and autoimmune diseases. Moreover, in recent years, an increasing number of studies identified a role for autophagy in the pathogenesis of skin diseases.
demonstrate alterations of the autophagic process in atopic dermatitis (AD) and psoriasis. Initial analyses suggested an increase in autophagic flux because high expression of the ATG5, ATG7, and ATG8, which are essential for autophagosomal elongation, was found in AD and psoriasis skin biopsies. Short-term treatment of human primary keratinocytes (KCs) with TNF-α, a central regulator of these inflammatory skin diseases, also confirmed an increase in the autophagic capacity. Surprisingly, AD and psoriasis biopsies as well as long-term TNF-α–treated KCs exhibited an accumulation of p62/SQSTM1, which is normally degraded during the autophagic process, indicating that despite the increased initiation of autophagosome formation, the processing of the cargo is impaired. Further analysis revealed that the amount and activity of cathepsins D and L, both components of the lysosome, were significantly decreased in long-term TNF-α–treated KCs and in lesional skin, indicating a functional impairment of autophagy in AD and psoriasis (Figure 1).
The consequences of diminished autophagy for the manifestations of inflammatory skin diseases are highly complex and are not well-understood. Because the differentiation of KCs depends on functional autophagy, decreased cathepsins D and L expression might contribute to the parakeratosis observed in psoriasis (
). Moreover, defects in autophagy and KC differentiation might be involved in the disturbed epithelial barrier that is present in psoriatic plaques. In fact, autophagy is regarded as a cell-autonomous antimicrobial defense mechanism in several epithelial tissues.
Another prominent function of autophagy in immunity is the inhibition of proinflammatory cytokine synthesis, including that of IL-1β and type-I interferons. Autophagy has been correlated with the degradation of central innate immune sensors such as cGAS, RIG-I, and TLR3 in various cell types (
). Autophagy also negatively regulates KC inflammatory responses through the scaffold protein p62/SQSTM1. The p62 protein is not only a cargo receptor for autophagy but also a multifunctional signaling hub for the activation of proinflammatory transcription factors, including NF-κB and NRF2 (
). A similar link between skin inflammation and autophagy is reflected by genetic variants of AP1S3, an autophagy regulator that has been found to be mutated in pustular psoriasis. KCs lacking AP1S3 not only reveal defective autophagy and p62 accumulation but also promote skin inflammation as a consequence of increased NF-κB activation and secretion of IL-1β and IL-36 (
). Several earlier GWASs had identified ATG16L1 as a susceptibility gene in Crohn’s disease and ankylosing spondylitis, suggesting that impaired autophagy might be a general feature contributing to the pathogenesis of autoinflammatory diseases.
It is uncertain whether the reactivation of normal autophagy could present a valid strategy for the treatment of psoriasis and other inflammatory skin diseases. The fact that some current antipsoriasis drugs, such as retinoids, are described to increase autophagy would support this hypothesis. However, other autophagy-mediated functions might be detrimental for the treatment of skin-related autoimmune diseases. For instance, the recognition of autoantigens presented by KCs is crucial for the development of psoriasis. Increased protein degradation through autophagy might increase the presentation of autoantigens and thus the activation of autoreactive T cells.
Hyperplasia of KCs is another hallmark of psoriasis. How increased autophagy, which constitutes an additional source of amino acids, nucleotides, and carbohydrates, will affect the survival and proliferation of KCs is unclear. Because inflammatory skin diseases are characterized by a tight interplay between KCs and various immune cells, such as T cells and dendritic cells, the effect of an autophagy activator on these cell types also has to be considered. Various studies show that TCR stimulation increases autophagy, whereas mice lacking essential regulators of autophagy exhibit reduced frequencies of thymocytes as well as CD4+ and CD8+ peripheral T cells (
). Thus, boosting autophagy in autoimmune diseases might promote T-cell survival and the inflammatory responses leading to exacerbation of the disease. In contrast, autophagy stimulation could reduce the secretion of IL-1β and IL-23 from antigen-presenting cells and hence prevent the differentiation of naive CD4+ T cells into the T helper type 17 lineage, which could have a beneficial impact on psoriasis treatment (
). Which effects of autophagy modulation on KCs and immune cells are dominant in the pathological situation should be carefully evaluated in in vivo models and will dictate the potential of autophagy modulators for the treatment of inflammatory skin diseases.
raises more questions than it answers. For instance, it will be interesting to investigate how other key cytokines involved in psoriasis and AD, including IL-17A or IL-4, influence autophagy, either alone or in combination with TNF-α. In addition, the downstream mediators in the TNF-α signaling pathway that inhibit autophagic flux as well as the exact target in the autophagic process remain unknown. It has also been found that p38 kinase, which is stimulated by TNF-α and upregulated in inflammatory skin disease, phosphorylates ATG5 and thereby inhibits the autophagic flux (
). It will be intriguing to investigate whether available gene-targeted mice deficient in autophagy regulators or selected cathepsins are hypersensitive to experimental psoriasis or AD. Finally, it will be most important to explore whether pharmacological activation of autophagy has beneficial effects on the treatment of inflammatory skin diseases.
Atopic dermatitis and psoriasis are frequent chronic inflammatory skin diseases. Autophagy plays a substantial role in the homeostasis of an organism. Loss or impairment of autophagy is associated with multiple diseases. To investigate the possibility that autophagy plays a role in atopic dermatitis and psoriasis, we investigated the levels of key ATG proteins in human skin specimens as well as in primary human epidermal keratinocytes exposed to inflammatory stimuli in vitro. Although TNF-α facilitated the induction of autophagy in an initial phase, it reduced the levels and enzymatic activities of lysosomal cathepsins in later time periods, resulting in autophagy inhibition.