Pathobiology of Chronic Inflammatory Skin Diseases: Interplay Between Keratinocytes and Immune Cells as a Target for Anti-Inflammatory Drugs

Albanesi, Cristina; Pastore, Saveria

doi:10.2174/138920010791196328

Cited by 77 publications

(67 citation statements)

References 187 publications

(241 reference statements)

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“…Although wound healing is accompanied by inflammatory reactions, chronic inflammation impairs acute wound healing. Furthermore, prolonged inflammation has been the bane of chronic dermatological conditions like psoriasis 1 and wound healing complications like non-healing diabetic wounds. 2 It is thus of great importance to understand the underlying regulation of skin inflammation.…”

mentioning

confidence: 99%

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

Lam

Tan

et al. 2011

Cell Death Differ

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Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor b-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)a pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-a treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBa signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBa pathway exhibited increased ROS production and TNF-a-or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.

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mentioning

confidence: 99%

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

Lam

Tan

et al. 2011

Cell Death Differ

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“…The etiology of these inflammatory atopic skin disorders is still obscure but it is basically autoimmune triggered and maintained by an aberrant response of the skin immune system cells [2]. Pro-inflammatory cytokines play a pivot role in the pathogenesis of immune skin pathologies [2,3].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Combined Colon Clear and Cupping Therapy on Idiopathic Skin Pathology

Nasrat¹,

Nasrat²,

Nasrat³

et al. 2015

Gen Med (Los Angel)

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The study aimed at demonstration of idiopathic skin pathology; influence of Helicobacter pylori and therapeutic effect of combined colon clear with cupping therapy.The complex spectrum of inflammatory skin diseases is ever expanding and evolving particularly in psoriasis, idiopathic eczema and atopic dermatitis. The etiology of these inflammatory atopic dermato-pathological disorders is still obscure but it is basically autoimmune triggered and maintained by an aberrant response of the skin immune system cells. Pro-inflammatory cytokines play a pivot role in the pathogenesis of immune skin pathologies. H. pylori could migrate or get forced to migrate to the colon leading to accumulation of profuse toxic amounts of ammonia unopposed or buffered by any acidity. The association of H. pylori with autoimmune disorders and chronic idiopathic dermatitis was sufficiently reported. The role played by the increased mucosal production of inflammatory mediators (cytokines) induced by H. pylori was also clearly illustrated. Antibiotics are seldom effective against extra-gastric H. pylori strains. A potent natural purgative is the only measure to eradicate H. pylori strains migrated to the colon. Elimination of toxic metabolites and inflammatory mediators from the body is a challenge which is only feasible via seroclearance blood-let out cupping therapy.Seven patients with atopic dermatitis, seven with idiopathic eczema and seven with psoriasis were randomly included in the study on the basis of being newly discovered, not starting any definitive treatment and having a frank history of H. pylori dyspepsia which was proved by sensitive specific tests. All patients underwent colon clear employing the potent natural senna purge which was followed in five days by a session of blood-let out seroclearance cupping therapy on the upper back.Marked improvement as regards the scales, itchiness and discoloration was seen in 5 patients with dermatitis, 6 patients with eczema and 4 patients with psoriasis after colon clear. Improvement was much more marked after cupping therapy.On conclusion, combined natural colon clear and blood-let out cupping therapy should be considered as a potent adjuvant therapeutic measure in idiopathic immune skin disorders associated with H. pylori.

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“…Other PDE4/PDE7 inhibitors based on heterospirocyclic compounds as well as the structurally related isoxazoline spirocycles diminish TNF-α release in vivo and in cell-based cultures respectively [144]. Another group of PDE inhibitors containing fused furane cycles including benzo [4,5]furo[3,2-c]pyridine derivatives (Glenmark Pharmaceuticals S.A. Mumbai, India) and structural anologues (Matrix Laboratories, Ltd., Secunderabad, India) have demonstrated whole-blood TNF-α inhibition [144].…”

Section: Isoxazoline Derivativesmentioning

confidence: 99%

“…In particular, it has become clear that the key immunologic role of epidermal keratinocytes in both the acute and chronic phases of skin inflammation is via cytokine production and surface molecule expression [1][2][3]. Prominent signaling pathways in inflammatory skin disease include the tumor necrosis factor (TNF) and interferon (IFN) pathways, as well as various interleukin pathways (reviewed in [4]). Much less studied is the potential role of the cyclic adenosine monophosphate (cAMP)-signaling pathway, a pathway with proven roles in resident epidermal and dermal immune cells [5], and defined immunosuppressive and anti-inflammatory actions [6].…”

Section: Introductionmentioning

confidence: 99%

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

Levy¹,

Zhou²

2015

J Clin Exp Dermatol Res

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The second messenger cyclic adenosine monophosphate (cAMP) regulates numerous key pathways that impact the immune system. Distinct cellular cAMP signaling pathways can lead to both pro-and anti-inflammatory effects depending upon the cell type. When dysregulated, these cAMP pathways can influence the pathogenesis of inflammatory cutaneous diseases, such as atopic dermatitis and psoriasis. In psoriasis and atopic dermatitis, cAMP and/or its effector proteins (e.g., protein kinase A) are downregulated suggesting that elevation of cAMP might be a therapeutic option. cAMP levels are the result of balance between synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Pharmacologically inhibiting PDEs represents one effective mechanism to raise intracellular cAMP levels perhaps leading to targeted immune suppression. Several drugs have been developed to target PDEs and while some toxicities (e.g., nausea and emesis) exist these drugs are generally well tolerated. Perhaps the best characterized is Apremilast, a PDE4 specific inhibitor, which has been FDA approved for the treatment of psoriasis and shows great promise as a safe and novel immunosuppressive medication. Following on the heels of Apremilast are numerous oral and topical PDE inhibitors in various stages of clinical trials. In this review, we examine the role of cAMP signaling in inflammatory cutaneous diseases and the development of PDE inhibitors as therapeutics.

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Pathobiology of Chronic Inflammatory Skin Diseases: Interplay Between Keratinocytes and Immune Cells as a Target for Anti-Inflammatory Drugs

Cited by 77 publications

References 187 publications

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

Therapeutic Effect of Combined Colon Clear and Cupping Therapy on Idiopathic Skin Pathology

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

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