Keratinocyte exosomes activate neutrophils and enhance skin inflammation in psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease that severely affects patients physiologically and psychologically. The pathogenesis involving communication between psoriatic keratinocytes and infiltrated immune cells such as neutrophils remains unclear. Exosomes are emerging mediators of intercellular communication. Herein we aim to investigate the release and function of psoriatic keratinocyte exosomes, which have not been illustrated to any extent. We first isolated exosomes from both healthy and psoriasis-like keratinocytes treated with psoriatic cytokine cocktail. These exosomes were observed to be endocytosed by neutrophils. Unlike non-cytokine-treated keratinocyte exosomes, cytokine-treated keratinocyte exosomes significantly induced NETosis (the process by which neutrophils produce and release neutrophil extracellular traps) and the expressions of IL-6, IL-8, and TNFa in neutrophils. Proteomic analysis showed that cytokine-treated keratinocyte exosomes exhibited a specific protein profile with proteins enriched in immune-related pathways. We then confirmed that NF-kB and p38 MAPK signaling pathways were activated in neutrophils stimulated by cytokine-treated keratinocyte exosomes and were responsible for the expressions of proinflammatory factors mentioned above. Finally, we verified in vivo that cytokine-treated keratinocyte exosomes participated in the skin lesion development of imiquimodinduced psoriasis-like mouse model. Collectively, we reveal that the release of exosomes works as a way of keratinocyte-neutrophil communication, indicating that keratinocyte exosomes, with their specific cargoes, are therapeutic candidates for psoriasis.-

The Immune Functions of Keratinocytes in Skin Wound Healing

“…Keratinocyte-derived exosomes can affect the dendritic cell phenotype and cytokine production [81]. Cytokine-treated keratinocytes secrete exosomes that promote neutrophil pro-inflammatory factor production, including IL-6, IL-8, and TNF-α [82].…”

Extracellular vesicles in Inflammatory Skin Disorders: from Pathophysiology to Treatment

“…As one early study revealed, IFN-α induced mast cells to release EVs that were capable of transferring cytoplasmic PLA2 activity to neighboring CD1a-expressing cells, which further led to the generation of neolipid antigens and subsequent recognition by CD1a-reactive T cells 11 , which established EVs as critical mediators in psoriasis. Our recent study demonstrated that EVs isolated from psoriatic cytokine-induced keratinocytes could be endocytosed by neutrophils and induced the latter to produce NETs and pro-inflammatory cytokines, thus exacerbating psoriatic inflammation 12 . Interestingly, neutrophils from patients with generalized pustular psoriasis secreted more EVs than those from controls, and further triggered keratinocytes to produce high levels of inflammatory molecules, such as IL-1β, IL-36G, IL-18 and TNF-α 82 .…”

“…Recent work from us and others has indicated that EVs play key immunomodulatory roles in the pathogenesis of various inflammatory skin diseases, such as psoriasis 11 , 12 , atopic dermatitis (AD) 13 , lichen planus (LP) 14 , bullous pemphigoid (BP) 15 , systemic lupus erythematosus (SLE) 16 , and chronic wound healing 7 . These inflammatory skin disorders pose major problems in dermatology given their complex pathophysiology and refractory nature, which ultimately pose a burden to the health, economic and social systems.…”

Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells

“…Relatedly, Jiang et al investigated the release and function of psoriatic keratinocyte-EXs and focused on the communication between keratinocytes and neutrophils [81]. In order to simulate psoriasis condition, keratinocytes were treated with psoriatic cytokine cocktail and then released exosomes from both healthy and psoriatic keratinocytes were characterized.…”

“…IL-8 is able to attract more neutrophils to the lesion site [82] and TNF-α can be found in many inflammatory diseases including psoriasis [84]. However, a specific cargo in psoriatic keratinocyte-EXs that might be responsible for stimulating the activation of neutrophils was not identified [81]. On the other hand, NF-kB and p38 MAPK signaling pathways were activated in neutrophils, induced by cytokine-treated keratinocyte-EXs and were responsible for the expressions of mentioned proinflammatory factors.…”