IL-17 Induces Inflammation-Associated Gene Products in Blood Monocytes, and Treatment with Ixekizumab Reduces Their Expression in Psoriasis Patient Blood

Wang, Claire Q.F.; Suárez‐Fariñas, Mayte; Nograles, Kristine; Mimoso, Claudia A.; Shrom, David; Dow, Ernst R.; Heffernan, Michael; Hoffman, Robert W.; Krueger, James G.

doi:10.1038/jid.2014.268

Cited by 52 publications

(47 citation statements)

References 27 publications

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“…For example, recent clinical trials have demonstrated a remarkable improvement of disease severity when IL-17A-and IL-17RA-targeting therapeutics are used (5,7,(39)(40)(41); and in January 2015, the first drug targeting IL-17A (secukinumab) was approved in the European Union and the United States for psoriasis treatment (8). In the imiquimod model, the expression of IL-17 signature genes such as S100a7a, S100a9, and Defb4 was only partially reduced in IL-17A-deficient mice, but highly reduced in IκBζ-deficient mice, also reflecting the inflammatory response seen in these mice as measured by ear thickness.…”

Section: Discussionmentioning

confidence: 99%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

132

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Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα-and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A-and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

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Section: Discussionmentioning

confidence: 99%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

132

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“…We do know that short-term treatment with anti-IL-23 significantly reduces circulating IL-17A levels, 65 whereas direct antagonism of IL-17A with ixekizumab can reduce expression of inflammation-related and cardiovascular risk genes in circulating leukocytes after only 2 weeks. 83 Links from modulation of inflammatory biomarkers to reductions in actual comorbid disease events still need be determined.…”

Section: Future Treatment Goalsmentioning

confidence: 99%

The translational revolution and use of biologics in patients with inflammatory skin diseases

Noda

Krueger

Guttman‐Yassky

2015

Journal of Allergy and Clinical Immunology

Self Cite

180

178

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“…Recently, Wang et al [77 ]demonstrated that the inflammatory state in human blood monocytes could be stimulated by IL-17. In addition, IL-17 may also promote monocyte adhesion by inducing molecules such as ICAM-1, integrin α4, platelet/endothelial cell adhesion molecule 1 and CD99.…”

Section: Innate Immunitymentioning

confidence: 99%

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

Khmaladze

Nandakumar

Holmdahl³

2015

Int Arch Allergy Immunol

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Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development.

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IL-17 Induces Inflammation-Associated Gene Products in Blood Monocytes, and Treatment with Ixekizumab Reduces Their Expression in Psoriasis Patient Blood

Cited by 52 publications

References 27 publications

IκBζ is a key driver in the development of psoriasis

IκBζ is a key driver in the development of psoriasis

The translational revolution and use of biologics in patients with inflammatory skin diseases

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

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