Antonios G.A. Kolios

IL-1β drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.

AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

Canakinumab in adults with steroid-refractory pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare, neutrophilic, ulcerative skin disease that is difficult to treat, especially when unresponsive to steroids.

Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man

Epidermal IL-15Rα, shed by keratinocytes upon stimulation with inflammatory cytokines, counteracts IL-15–induced proliferation of IL-17–producing T cells to dampen psoriatic skin disease.

Low-Dose Excimer 308-nm Laser for Treatment of Lichen Planopilaris

L ichen planopilaris (LPP) is a difficult-to-treat, chronic, inflammatory autoimmune disease targeting the hair follicle that eventually leads to permanent irreversible scarring alopecia. It commonly affects adult women on the central scalp with multifocal patches, perifollicular erythema, hyperkeratosis, and subjective complaints like pruritus or pain. Recently, a deficiency of the peroxisome proliferatoractivated receptor (PPAR) and disturbed lipid metabolism in the pilosebaceous unit were identified in LPP, with subsequent lymphocyte recruitment and upregulated cytokine expression provoking loss of adhesion of follicular keratinocytes. Based on this finding, treatment with the PPAR agonist pioglitazone was successfully tried in some cases, in addition to other current treatment options such as intralesional steroids, doxycycline, hydroxychloroquine, mycophenolate mofetil. For chronic inflammation, we hypothesized that UV-B excimer laser treatment might also be effective in LPP, since it has proven beneficial for certain inflammatory skin disorders that are mediated by lymphocytes and are responsive to psoralen plus UV-A therapy.

Counter-regulation of T cell effector function by differentially activated p38

Distinct mechanisms of p38 activation have opposing effects on T cell responses through differential regulation of NFATc1 activity.

Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1β after Azathioprine Exposure: Case Report and Review of the Literature.

Sweets syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1β (IL-1β) mRNA in lesional skin, and immunohistochemistry high levels of IL-1β at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein.

Identification of a novel PPARβ/δ/miR‐21‐3p axis in UV‐induced skin inflammation

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV‐induced skin cancer development. Here, we describe a novel PPARβ/δ‐dependent molecular cascade involving TGFβ1 and miR‐21‐3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR‐21‐3p, that we identify as a novel UV‐induced miRNA in the epidermis, plays a pro‐inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR‐21‐3p reduces UV‐induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA‐based topical therapies for cutaneous disorders.

Swiss S1 Guidelines on the Systemic Treatment of Psoriasis Vulgaris

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a prevalence of 1.5-2% in Western industrialized countries. A relevant percentage of patients suffer from moderate-to-severe psoriasis and experience a significant reduction in quality of life. The choice of an adequate therapy could help to prevent disease and exacerbation of comorbidity, which could increase quality of life, avoid hospitalization and avoid reduction of working days. The present guidelines are focused on the initiation and management of systemic therapies in cases of moderate-to-severe plaque-type psoriasis in adults to optimize treatment response, adherence and quality of life. This first version of the Swiss S1 guidelines presents therapeutic recommendations which are based on a systematic literature search as well as an informal expert consensus of dermatologists in Switzerland.

Cutaneous Corynebacterium Infection Presenting with Disseminated Skin Nodules and Ulceration

In the context of the European migrant crisis, more and more cases of cutaneous diphtheria are seen. A typical presentation includes painful cutaneous ulcerations with grayish-whitish pseudomembranes. Here we present 2 male Eritrean patients suffering from cutaneous nontoxigenic Corynebacterium diphtheriae (patient 1) and Corynebacterium striatum (patient 2) infection.