Protection from Psoriasis-Related Thrombosis after Inhibition of IL-23 or IL-17A

Li, Yumeng; Golden, Jackelyn B.; Camhi, Maya I.; Zhang, Xiufen; Fritz, Yi; Diaconu, Doina; Ivanco, Tammy L.; Simon, Daniel I.; Kikly, Kristine; McCormick, Thomas S.; Wang, Yunmei; Ward, Nicole L.

doi:10.1016/j.jid.2017.09.021

Cited by 31 publications

(31 citation statements)

References 40 publications

(57 reference statements)

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“…Further supporting this therapeutic strategy, antibodies to IL-17A or the IL-17 receptor A subunit lowered blood pressure by 30 mm Hg and ameliorated vascular inflammation in a model of AngII-induced arterial hypertension (Saleh et al, 2016). Moreover, Li et al (2018) recently described that arterial thrombus formation was attenuated in a mouse model of psoriasis under IL-17A inhibition, indicating that targeting cytokines that mediate psoriatic inflammation may indeed improve cardiovascular comorbidities. Our data demonstrate that psoriasisassociated vascular inflammation/dysfunction can potentially be cured and prevented by anti-IL-17A treatment.…”

Section: Discussionmentioning

confidence: 89%

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis

Schüler

Brand

Klebow

et al. 2019

Journal of Investigative Dermatology

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Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. IL-17A plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis. We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i) K14-IL-17A ind/þ mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17A ind/ind and heterozygous CD11c-IL-17A ind/þ mice overexpressing IL-17A in CD11c þ cells, leading to a delayed onset of moderate psoriasis-like skin disease; and (iii) the acute model of imiquimodinduced psoriasis-like skin inflammation. Similar to the severity of skin disease, vascular dysfunction correlated with peripheral IL-17A levels and neutrophil infiltration into the aortic vessel wall. Successful anti-IL-17A treatment of psoriatic skin lesions diminished peripheral oxidative stress levels, proinflammatory cytokines, and vascular inflammation. These data highlight the pivotal role of IL-17A linking the development of skin lesions and vascular disease in psoriasis. Anti-IL-17A therapy might thus represent a useful approach to attenuate and prevent vascular disease in psoriasis patients.

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Section: Discussionmentioning

confidence: 89%

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis

Schüler

Brand

Klebow

et al. 2019

Journal of Investigative Dermatology

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“…In a murine model of IL-17A overexpression, neutralization of cytokines downstream of IL-17A improved vascular health [ 139 ]. Additionally, anti-IL-17A monoclonal antibodies prevented vascular disease in a murine model of psoriasis [ 140 ]. In humans, an acute myocardial infarction registry demonstrated that serum IL-17A below a median of 6.26 pg/mL was associated with higher risk for all-cause mortality and recurrent myocardial infarction, but many patients had IL-17A levels below the assay’s detection limit of 2.5 pg/mL [ 141 ].…”

Section: Expanding Our Understanding Of the Immunologic Role Of Il-17mentioning

confidence: 99%

The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis

Blauvelt

Chiricozzi

2018

Clinic Rev Allerg Immunol

516

370

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Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.

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“…Treatment attenuated acanthosis in correlation with lengthening time to occlusive thrombus formation (with similar results to those from wild-type controls), supports a common pathogenic pathway for both conditions. 66…”

Section: Psoriasis and Cardiovascular Diseases: What Is The Place Formentioning

confidence: 99%

The role of the interleukin‐23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

Egeberg

Gisondi

Carrascosa

et al. 2020

Acad Dermatol Venereol

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Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been identified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemiological observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleterious effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in b-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related proinflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients.

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Protection from Psoriasis-Related Thrombosis after Inhibition of IL-23 or IL-17A

Cited by 31 publications

References 40 publications

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis

The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis

The role of the interleukin‐23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

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