JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis

Klaeschen, Anna Sophie; Nümm, Tim Joachim; Herrmann, Nadine; Leib, Nicole; Maintz, Laura; Sakai, Takashi; Wenzel, Joerg; Bieber, Thomas

doi:10.1016/j.jaci.2020.11.041

Cited by 23 publications

(20 citation statements)

References 52 publications

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“…Owing to its particular activity against all JAKs and the spleen tyrosine kinase (SYK), cerdulatinib was initially developed as a systemic therapy for haematological malignancies 228 . Besides T cell activation, SYK is a crucial signalling molecule for the high-affinity receptor for IgE (FcεRI) expressed on epidermal Langerhans cells and inflammatory dendritic epidermal cells [229][230][231] . Therefore, simultaneous targeting of JAKs and SYK by cerdulatinib appears to be an appealing strategy for topical pharmacological intervention in AD.…”

Section: The Broad Approach With Jak Inhibitorsmentioning

confidence: 99%

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

Bieber

2021

Nat Rev Drug Discov

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Section: The Broad Approach With Jak Inhibitorsmentioning

confidence: 99%

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

Bieber

2021

Nat Rev Drug Discov

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359

294

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“…Roles of Langerhans cells, and inflammatory dendritic epidermal cells (IDEC) in AD have been reported ( Klaeschen et al, 2021 ; Marschall et al, 2021 ). It would be necessary to examine interactions between mast cells, Langerhans cells, and IDECs by employing culture medium and transwell assays.…”

Section: Discussionmentioning

confidence: 99%

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

et al. 2021

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Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.

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“…IDECs play a major role in the development of AD, and inhibition of their activation is a focal point of current therapeutics. Jak kinases are important for the development of DCs, and the inhibition of JAK1/JAK2 has been shown to disrupt the development of IDECs from monocytes [62]. The DCs with high-affinity IgE receptors (FcεRI + ) in AD skin are important for initiating the immune response to protein antigens entering the epidermis [21,63].…”

Section: Innate Immunity In Atopic Dermatitismentioning

confidence: 99%

Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis

Kader

Azeem

Jwayed

et al. 2021

Cells

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Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.

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JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis

Cited by 23 publications

References 52 publications

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis

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