Antagonistic effect of the inflammasome on thymic stromal lymphopoietin expression in the skin

Schuepbach‐Mallepell, Sonia; Philippe, Virginie; Brüggen, Marie‐Charlotte; Watanabe, Hideki; Roques, Stéphanie; Baldeschi, Christine; Gaide, Olivier

doi:10.1016/j.jaci.2013.06.033

Cited by 19 publications

(17 citation statements)

References 34 publications

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“…Next, we investigated the effect of ox-LDL on cultured TECs in vitro and observed that ox-LDL attenuated TSLP expression on TECs through the activation of RXRA and IL-1b. These findings are consistent with previous studies [27], showing that IL-1b inhibits TSLP expression on skin epithelial cells. Indeed, RXRA, a type of nuclear receptor, has been implicated in the suppression of TSLP expression in mouse keratinocytes [28].…”

Section: Discussionsupporting

confidence: 94%

“…It has previously been demonstrated that induction of nuclear receptor (RXRA) and inflammasome IL-1b can inhibit TSLP expression on keratinocytes [27,28]. And that ox-LDL activates endothelial cells and smooth muscle cells with up-regulation of IL-1 [29,30], and its effect on TDEC is not clear.…”

Section: The Inhibition Of Tslp Expression On Ex Vivo Thymus-derived mentioning

confidence: 99%

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Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice

Mao

Meng

et al. 2015

Atherosclerosis

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Section: Discussionsupporting

confidence: 94%

Section: The Inhibition Of Tslp Expression On Ex Vivo Thymus-derived mentioning

confidence: 99%

Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice

Mao

Meng

et al. 2015

Atherosclerosis

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“…DNCB triggers a T cell independent inflammatory response through activation of the NALP-3 inflammasome in keratinocytes (Schuepbach-Mallepell et al , 2013), and has been used to treat HPV associated-genital warts. Despite its efficacy, this chemical is potentially mutagenic and carcinogenic (Black et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus E7 Oncoprotein Transgenic Skin Develops an Enhanced Inflammatory Response to 2,4-Dinitrochlorobenzene by an Arginase-1-Dependent Mechanism

Tran

Bergot

Mattarollo

et al. 2014

Journal of Investigative Dermatology

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We have shown that expression of Human Papillomavirus type 16 E7 (HPV16.E7) protein within epithelial cells, as occurs in HPV associated-premalignancy and cancers, results in local immune suppression, and a weak and ineffective immune response to E7 protein. However, a robust acute inflammatory stimulus can overcome this to enable immune elimination of HPV16.E7 transformed epithelial cells. 2,4-Dinitrochlorobenzene (DNCB) can elicit acute inflammation and has been shown to initiate the regression of HPV-associated genital warts. Although clinical use of DNCB is discouraged due to its mutagenic potential, understanding how DNCB induced acute inflammation alters local HPV16.E7 mediated-immune suppression might lead to better treatments. Here, we show that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, not seen in non-transgenic control animals. The E7 associated-inflammatory response is characterized by enhanced expression of Th2 cytokines and increased infiltration of CD11b+Gr1intF4/80+Ly6ChiLy6Glow myeloid cells, producing arginase-1. Inhibition of arginase with an arginase specific inhibitor, N(omega)-hydroxy-nor-L-arginine, ameliorates the DNCB-induced inflammatory response. Our results demonstrate that HPV16.E7 protein enhances DNCB associated-production of arginase-1 by myeloid cells and consequent inflammatory cellular infiltration of skin.

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“…DNCB triggers a T-cell-independent inflammatory response through the activation of the NALP-3 inflammasome in keratinocytes (147), and it has been used to treat HPVassociated genital warts. Despite its efficacy, this chemical is potentially mutagenic and carcinogenic (66).…”

Section: Discussionmentioning

confidence: 99%

“…DNCB has been described as a "danger signal" which can trigger the NALP-3 inflammasome in keratinocytes or DC (91,147,194), resulting in production of proinflammatory cytokines including IL-6, IL-1β during early inflammatory response (148, 149). We indeed detected T and B lymphocyte-independent induction of IL-6 and IL-1β mRNA in DNCB-treated K14E7 skin, indicating the possible contribution of these cytokines in regulating the hyperinflammation.…”

Section: Hpv16e7-induced Cutaneous Hyperinflammation To Dncb Is Assomentioning

confidence: 99%

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Tran¹

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Persistent infection with oncogenic human papillomaviruses (HPV), particularly HPV16, is associated with selective expression of two virally encoded proteins (E6 and E7). One action of HPV16.E7 protein is to subvert the innate immune system through the down-regulation of IFNγ pathways, modulation of antigen presentation, and suppression of Toll-like receptor 9 protein.K14.E7 transgenic mice, which express HPV16.E7 oncoprotein within basal keratinocytes under the control of the keratin 14 transcriptional promoter, have been extensively used as a model of HPV oncoprotein-induced immune suppression associated with human squamous cancers, in which only the E6 and E7 genes of the papillomavirus are expressed. It has previously been shown that skin grafts expressing HPV16.E7 oncoprotein are not spontaneously rejected when transplanted onto syngeneic animals, but they are rejected when certain components of the innate immune system are unavailable, confirming that the expression of HPV16.E7 in the epithelium results in the establishment of a local suppressive environment and the subversion of antigen-specific T cells. Therefore, successful strategies targeting HPV-associated cancer need to circumvent or disrupt the local suppressive environment.Topical immunotherapy with immunostimulatory agents has been used clinically to treat cancerous lesions including squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. Topical application of 2,4-dinitrochlorobenzene (DNCB) is an effective therapy for condylomata acuminata caused by HPV infection. DNCB induced the complete clearance of HPV-associated warts in 13/15 patients. However, the use of DNCB for treatment has been discouraged because of its mutagenic potential. The aim of my doctoral research is to understand the mechanism of DNCB-induced inflammation in K14.E7 transgenic mice which has been poorly understood. I hypothesized that understanding how induction of a vigorous acute inflammatory response by DNCB can break the local immune-suppressive environment and restore the effector function of adaptive immunity might lead to more acceptable treatments for persisting HPV infection. In support of this hypothesis, the present study showed that DNCB application along with E7 specific immunization therapy was capable of inducing HPV16.E7 skin graft rejection.Arginase, which metabolizes l-arginine to N-ornithine and urea, has been identified as a crucial regulator of inflammation. As inflammation decides the fate of HPV infection and arginase is an important regulator of inflammation and immunity, I investigated the ii interaction between DNCB-induced inflammation and HPV16.E7 protein in the induction of arginase in K14.E7 transgenic mice. The first part of this study showed that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, which is not seen in nontransgenic control animals. The E7-associated Taken together, my study suggests that HPV16.E7 protein enhances DNCB associated-prod...

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Antagonistic effect of the inflammasome on thymic stromal lymphopoietin expression in the skin

Cited by 19 publications

References 34 publications

Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice

Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice

Human Papillomavirus E7 Oncoprotein Transgenic Skin Develops an Enhanced Inflammatory Response to 2,4-Dinitrochlorobenzene by an Arginase-1-Dependent Mechanism

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

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