Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation

Gui, Jun; Gober, Michael D.; Yang, Xiao‐Ping; Katlinski, Kanstantsin V.; Marshall, Christine; Sharma, Monica; Werth, Victoria P.; Baker, Darren P.; Rui, Hallgeir; Seykora, John T.; Fuchs, Serge Y.

doi:10.1016/j.jid.2016.06.608

Cited by 29 publications

(27 citation statements)

References 41 publications

(76 reference statements)

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“…Tight binding is not always an advantage, as is shown by a number of human diseases that are enhanced by elevated IFN-1 signaling. Examples include lupus, tuberculosis, AIDS, psoriatic skin inflammation, and cognitive decline (7,(31)(32)(33)(34)(35). A number of approaches have been taken to circumvent increased IFN-1 signaling, particularly in lupus.…”

Section: The Varying Binding Affinities Of Ifn-1s and Their Functionamentioning

confidence: 99%

The molecular basis for differential type I interferon signaling

Schreiber

2017

Journal of Biological Chemistry

190

184

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Type I interferons (IFN-1) are cytokines that affect the expression of thousands of genes, resulting in profound cellular changes. IFN-1 activates the cell by dimerizing its two-receptor chains, IFNAR1 and IFNAR2, which are expressed on all nucleated cells. Despite a similar mode of binding, the different IFN-1s activate a spectrum of activities. The causes for differential activation may stem from differences in IFN-1-binding affinity, duration of binding, number of surface receptors, induction of feedbacks, and cell type-specific variations. All together these will alter the signal that is transmitted from the extracellular domain inward. The intracellular domain binds, directly or indirectly, different effector proteins that transmit signals. The composition of effector molecules deviates between different cell types and tissues, inserting an additional level of complexity to the system. Moreover, IFN-1s do not act on their own, and clearly there is much cross-talk between the activated effector molecules by IFN-1 and other cytokines. The outcome generated by all of these factors (processing step) is an observed phenotype, which can be the transformation of the cell to an antiviral state, differentiation of the cell to a specific immune cell, senescence, apoptosis, and many more. IFN-1 activities can be divided into robust and tunable. Antiviral activity, which is stimulated by minute amounts of IFN-1 and is common to all cells, is termed robust. The other activities, which we term tunable, are cell type-specific and often require more stringent modes of activation. In this review, I summarize the current knowledge on the mode of activation and processing that is initiated by IFN-1, in perspective of the resulting phenotypes.

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Section: The Varying Binding Affinities Of Ifn-1s and Their Functionamentioning

confidence: 99%

The molecular basis for differential type I interferon signaling

Schreiber

2017

Journal of Biological Chemistry

190

184

View full text Add to dashboard Cite

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“…It was recently shown that AMP LL37 enables keratinocytes to produce IFN-β in response to dsRNA from dying cells 42 , 43 . In our study, CXCL10 upregulation in psoriatic skin may indicate enhanced IFN-signalling in psoriasis, and therapeutic IFNAR removal has proven to be effective in psoriatic skin inflammation treatment by UV phototherapy 44 . Moreover, AIM2, an innate receptor binding to dsDNA, was expressed at increased levels in psoriatic skin in our study, consistent with previous reports 41 , 45 , 46 .…”

Section: Discussionmentioning

confidence: 53%

Signs of innate immune activation and premature immunosenescence in psoriasis patients

Šahmatova

Sügis

Šunina

et al. 2017

Sci Rep

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Psoriasis is a chronic inflammatory disease that affects skin and is associated with systemic inflammation and many serious comorbidities ranging from metabolic syndrome to cancer. Important discoveries about psoriasis pathogenesis have enabled the development of effective biological treatments blocking the T helper 17 pathway. However, it has not been settled whether psoriasis is a T cell-mediated autoimmune disease or an autoinflammatory disorder that is driven by exaggerated innate immune signalling. Our comparative gene expression and hierarchical cluster analysis reveal important gene circuits involving innate receptors. Innate immune activation is indicated by increased absent in melanoma 2 (AIM2) inflammasome gene expression and active caspase 1 staining in psoriatic lesional skin. Increased eomesodermin (EOMES) expression in lesional and non-lesional skin is suggestive of innate-like virtual memory CD8+ T cell infiltration. We found that signs of systemic inflammation were present in most of the patients, correlated with the severity of the disease, and pointed to IL-6 involvement in the pathogenesis of psoriatic arthritis. Among the circulating T cell subpopulations, we identified a higher proportion of terminally differentiated or senescent CD8+ T cells, especially in patients with long disease duration, suggesting premature immunosenescence and its possible implications for psoriasis co-morbidities.

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“…The role of pDC and IFN-I in the IMQ psoriasiform dermatitis model is controversial in addition to the source of IFN-I production 4 , 5 , 20 , 22 , 23 . Therefore, we examined an alternative target which may also be inhibited therapeutically to treat TLR-pDC driven immune pathology, slc15a4 .…”

Section: Resultsmentioning

confidence: 99%

“…The role of IFN-I in the IMQ model of psoriasiform dermatitis is controversial 5 , 20 , 22 , 23 . The most potent producer of IFN-I is the very rare pDC cell type.…”

Section: Discussionmentioning

confidence: 99%

“…pDC production of IFN-I is an expected dramatic component of the IMQ model and critical to initiate psoriasis in a xenograft model 4 . However, deficiency of the IFN-I receptor was reported to have no effect in two IMQ studies 5 , 20 , while two subsequent IMQ studies demonstrated a significant role for the IFN-I receptor (IFNAR1) 22 , 23 . Similarly, pDC which are responsible for ~50% of all acute IFN-I 24 has been implicated in psoriasis 4 and the IMQ psoriasiform model.…”

Section: Introductionmentioning

confidence: 99%

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A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice

Griffith

Zaidi

Pietro

et al. 2018

Sci Rep

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There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4feeble except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.

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Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation

Cited by 29 publications

References 41 publications

The molecular basis for differential type I interferon signaling

The molecular basis for differential type I interferon signaling

Signs of innate immune activation and premature immunosenescence in psoriasis patients

A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice

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