IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Belle, Astrid B. Van; Heusch, Magali de; Lemaire, Muriel M.; Hendrickx, Emilie; Warnier, Guy; Dunussi-Joannopoulos, Kyri; Fouser, Lynette A.; Renauld, Jean‐Christophe; Dumoutier, Laure

doi:10.4049/jimmunol.1102224

Cited by 254 publications

(254 citation statements)

References 54 publications

(60 reference statements)

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…Overexpression of IL-22 results in psoriasis-like skin alterations in mice (36), and IL-22 deficiency protects mice from imiquimodinduced psoriasis-like skin inflammation (37). Here, we show that IL-22 is highly reduced in IκBζ-deficient mice receiving imiquimod, whereas IL-22 expression remains unaltered in IL-17A-deficient mice treated with imiquimod.…”

Section: Discussionmentioning

confidence: 58%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

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

101

132

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 58%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

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

101

132

View full text Add to dashboard Cite

show abstract

“…IL-17 and G-CSF have an impact on keratinocytes resulting in their proliferation, whereas S100A8/A9 and CXCL1 are strong chemoattractants for neutrophils. The observed local inflammatory changes and epidermal hyperplasia are reminiscent of psoriasis 8,23,32,47 . Hyperproliferation and psoriatic plaques induced by Aldara have primarily been ascribed to cytokines, such as IL-17 (refs 8,22) and IL-22 (ref.…”

Section: Discussionmentioning

confidence: 97%

“…Currently, repeated topical application of Aldara is considered a valuable mouse model for psoriasis 22 , which is an inflammatory and hyperproliferative condition of the skin. In psoriasis patients as well as in Aldaratreated mice, pDCs and neutrophils have been demonstrated to infiltrate the lesion site, and the cytokines IL-17, IL-22 and IL-23, as well as the presence of gd-T cells, are considered as being important 8,[23][24][25] .…”

mentioning

confidence: 99%

Aldara activates TLR7-independent immune defence

et al. 2013

View full text Add to dashboard Cite

Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

show abstract

“…For example, in addition to IL-17A and IL-23, IL-22 has been shown to be important in IL-23-induced skin inflammation (40) and IMQinduced psoriasiform skin inflammation (41). It should be noted that blocking Th17 signature gene expression could have adverse effects such as increased risk for infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

129

123

View full text Add to dashboard Cite

IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

show abstract

IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Cited by 254 publications

References 54 publications

IκBζ is a key driver in the development of psoriasis

IκBζ is a key driver in the development of psoriasis

Aldara activates TLR7-independent immune defence

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Contact Info

Product

Resources

About