KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Billi, Allison C.; Ludwig, J.; Fritz, Yi; Rozic, Richard; Swindell, William R.; Tsoi, Lam C.; Gruzska, Dennis; Abdollahi‐Roodsaz, Shahla; Xing, Xianying; Diaconu, Doina; Uppala, Rattapon; Camhi, Maya I.; Klenotic, Philip A.; Sarkar, Mrinal K.; Husni, M. Elaine; Scher, Jose U.; McDonald, Christine; Kahlenberg, J. Michelle; Midura, Ronald J.; Guðjónsson, Jóhann E.; Ward, Nicole L.

doi:10.1172/jci133159

Cited by 39 publications

(35 citation statements)

References 17 publications

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“…43,44 Transgenic overexpression of certain molecules (mostly in basal or suprabasal keratinocytes) is another approach to investigate their role in chronic inflammation. The heterogeneous group of molecules whose epidermal overexpression resulted in such phenotypes includes transforming growth factor alpha (TGF-a), 45 IL-6, 46 IL-1a, 47 IFN-g, 48 vascular endothelial growth factor (VEGF), 49,50 latent human TGF-b1 51 (Fig 2), bone morphogenic protein (BMP)-6, 52 angiogenesis-related tyrosine kinase with immunoglobulin-like and EGF-like domains-2 (Tie2), 53,54 p40 (the common subunit of IL-12 and IL-23), 55 amphiregulin, 56 collagenase, 57 MEK1 (an MAP kinase upstream of Erk), 58 human a 2 , a 5 , or b 1 integrin subunits, 59 Ras-related C3 botulinum toxin substrate 1, 60 kallikrein-related peptidase 6, 61 and IL-17C. 47 As exemplified by TGF-b1 transgenic mice, such models may be used for preclinical therapeutic studies.…”

Section: Genetically Engineered Animalsmentioning

confidence: 99%

Animal models of psoriasis—highlights and drawbacks

Schön

Manzke

Erpenbeck

2021

Journal of Allergy and Clinical Immunology

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Research into the pathophysiology of psoriasis remains challenging, because this disease does not occur naturally in laboratory animals. However, specific aspects of its complex immune-pathology can be illuminated through transgenic, knockout, xenotransplantation, immunological reconstitution, drug-induced, or spontaneous mutation models in rodents. Although some of these approaches have already been pursued for more than 5 decades and even more models have been described in recent times, they have surprisingly not yet been systematically validated. As a consequence, researchers regularly examine specific aspects that only partially reflect the complex overall picture of the human disease. Nonetheless, animal models are of great utility to investigate inflammatory mediators, the communication between cells of the innate and the adaptive immune systems, the role of resident cells as well as new therapies. Of note, various manipulations in experimental animals resulted in rather similar phenotypes. These were called ''psoriasiform'', ''psoriasis-like'' or even ''psoriasis'' usually on the basis of some similarities with the human disorder. Xenotransplantation of human skin onto immunocompromised animals can overcome this limitation only in part. In this review, we elucidate approaches for the generation of animal models of psoriasis and assess their strengths and limitations with a certain focus on more recently developed models.

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Section: Genetically Engineered Animalsmentioning

confidence: 99%

Animal models of psoriasis—highlights and drawbacks

Schön

Manzke

Erpenbeck

2021

Journal of Allergy and Clinical Immunology

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“…PAR1 deficient mice showed decreased cartilage degradation and lower levels of synovial cytokine mRNA and MMP-13 mRNA in a model of antigen-induced arthritis 20 . PAR1 deficiency is also protective in a model of psoriatic arthritis driven by increased dermal expression of kallikrein 6 58 . In contrast, PAR1 deficiency did not afford significant protection in the destabilization of the medial meniscus (DMM) model of OA 19 .…”

Section: Discussionmentioning

confidence: 99%

Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids

Chandrabalan

Firth

Litchfield

et al. 2020

Preprint

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Objective: Osteoarthritis (OA) is the most prevalent joint disorder with incidence increasing worldwide. Mechanistic insights into OA pathophysiology are still evolving and there are currently no disease-modifying OA drugs available. It is well established that an increase in proteolytic enzyme activity is linked to progressive degradation of the cartilage in OA. Proteolytic enzymes can also trigger inflammation through activation of a family of G-protein coupled receptors (GPCRs) called the Proteinase Activated Receptors (PARs). Here we sought to characterize the PAR activating enzyme repertoire in human OA knee joint fluids. Methods: Human knee joint synovial fluids derived from twenty-five OA patients and four healthy donors were screened for PAR cleavage activity using novel genetically encoded human PAR biosensor expressing cells. The class or type of enzymes cleaving the PARs was further characterized using enzyme-selective inhibitors and enzyme-specific fluorogenic substrates. Results: Activity of PAR1, PAR2 and PAR4 activating enzymes were identified at substantially different levels in OA patients relative to healthy knee joint synovial fluids. Using enzyme class or type selective inhibitors and fluorogenic substrates we found that serine proteinases, including thrombin-like enzymes, trypsin-like enzymes, and matrix metalloproteinases are the major PAR activating enzymes present in the OA knee synovial fluids. Conclusions: Multiple enzymes activating PAR1, PAR2 and PAR4 are present in OA joint fluids. PAR signalling can trigger pro-inflammatory responses and targeting PARs has been proposed as a therapeutic approach in OA. Knowledge of the PAR activators present in the human knee joint will guide study of relevant signaling events and enable future development of novel PAR targeted therapies for OA and other inflammatory joint diseases.

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“…Cathepsin S, a lysosomal cysteine protease that takes part in the degradation of damaged or unwanted proteins, has been identified as one of the major IL-36γ–activating proteases in the skin ( 130 ), thereby initiating and amplifying skin-associated inflammatory responses. Recently, Billi et al determined that epidermal kallikrein-related peptidase 6 (KLK6), a secreted serine protease, promotes development of psoriasis and psoriatic arthritis-like joint inflammation via protease-activated receptor 1–dependent (PAR1-dependent) signaling ( 131 ).…”

Section: Keratinocytes: Source and Target Of Inflammatory Mediatorsmentioning

confidence: 99%

Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin

et al. 2020

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The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

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KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Cited by 39 publications

References 17 publications

Animal models of psoriasis—highlights and drawbacks

Animal models of psoriasis—highlights and drawbacks

Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids

Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin

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