Epidermal NLRP10 contributes to contact hypersensitivity responses in mice

Damm, A.; Giebeler, Nives; Zamek, Jan; Zigrino, Paola; Kufer, Thomas A.

doi:10.1002/eji.201646401

Cited by 27 publications

(22 citation statements)

References 34 publications

(58 reference statements)

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“…However, in the current study, we did not observe any increase in caspase-1 activation or IL-1b production in PYNOD-KO macrophages in response to inflammasome activators or microbial infection. Our current results are consistent with recent reports (6) and suggest that the basal PYNOD expression in macrophages is not essential for determining the magnitude of these responses. The apparent discrepancy of our previous and current results can be explained by the presence of redundant regulatory mechanisms for caspase-1 activation (18,19).…”

Section: Discussionsupporting

confidence: 83%

“…The basal expression of PYNOD in human skin is also high (23). Recently, Damm et al (6) reported that total and epidermis-specific PYNOD-KO mice exhibit defects in the T cell-mediated inflammatory response using the DNFB-induced CHS model. They also observed a significant reduction in T cell infiltration in the inflamed ear skin of the total but not the epidermal-specific PYNOD-KO mice in this model, suggesting that the epidermal and nonepidermal PYNOD contribute to CHS by different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…It was recently reported that PYNOD contributes to T cell-mediated delayed-type hypersensitivity in a CHS model (6). In addition, a genome-wide association study identified a genomic locus including Nlrp10, the PYNOD-encoding gene, as a susceptibility locus for atopic dermatitis in humans (13).…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

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Characterization of Innate and Adaptive Immune Responses in PYNOD-Deficient Mice

et al. 2018

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PYNOD (also called NLRP10) is a member of the nucleotide-binding domain and leucine-rich repeat containing family. Many members of this family play important roles in the activation and/or regulation of immune and inflammatory responses. We previously showed that PYNOD inhibits the IL-1b secretion in response to microbial infection in PYNOD-transgenic mice. In this study, we generated PYNOD-knockout (KO) mice and further investigated PYNOD's role in the innate and adaptive immune responses. Similar to wild-type macrophages, PYNOD-KO macrophages produced IL-1b and induced pyroptosis, a caspase-1-dependent programmed cell death, in response to various inflammasome activators and microbial infection. In addition, the PYNOD deficiency did not significantly affect the proliferation or cytokine production of T cells, the delayed-type hypersensitivity responses, the anti-tumor immunity, the Ag-specific Ab production, the cytotoxicity of NK cells, or the maturation, Ag-presenting capacity, or elicited migration of dendritic cells. Furthermore, the steady-state skin self-antigen transport to regional lymph nodes was not impaired in PYNOD-KO mice, suggesting that PYNOD is dispensable for steady-state dendritic cell migration. These results suggested that PYNOD is dispensable for the regulation of innate and adaptive immune responses in mice, unless PYNOD's expression is highly induced under certain conditions. ImmunoHorizons, 2018, 2: 129-141.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Characterization of Innate and Adaptive Immune Responses in PYNOD-Deficient Mice

et al. 2018

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“…NOD‐like receptor family pyrin domain containing 10 (NLRP10), which lacks the leucine‐rich domain present in pro‐inflammatory NLRPs, inhibits inflammation and is predominantly expressed in terminally differentiated keratinocytes (Figure , right panel; Figure ) . Knockout of NLRP10 did not impair epidermal cornification but reduced contact hypersensitivity responses in mice . Interestingly, caspase‐14 and gasdermin A are further keratinocyte differentiation‐specific proteins that are closely related to pyroptosis factors.…”

Section: Epidermal Keratinocytes Suppress Inflammation During Normal mentioning

confidence: 99%

“…[33] Knockout of NLRP10 did not impair epidermal cornification but reduced contact hypersensitivity responses in mice. [49] Interestingly, caspase-14 [50][51][52] and gasdermin A [33][34][35][36]53] are further keratinocyte differentiation-specific proteins that are closely related to pyroptosis factors. Caspase-14 has evolved from caspase-1 and caspase-15 [52] but in contrast to those lacks a CARD or pyrin domain.…”

Section: Epidermal Ker Atino C Y Te S Suppre Ss Infl Ammation Durinmentioning

confidence: 99%

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

Eckhart

Tschachler

2018

Experimental Dermatology

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The function of the skin as a barrier to the environment is mainly achieved by the outermost layers of the epidermis. In the granular layer, epidermal keratinocytes undergo the last steps of their terminal differentiation program resulting in cornification. The coordinated conversion of living keratinocytes into corneocytes, the building blocks of the cornified layer, represents a unique form of programmed cell death. Recent studies have identified numerous genes that are specifically expressed in terminally differentiated keratinocytes and, surprisingly, this genetic program does not only include mediators of cornification but also suppressors of pyroptosis, another mode of programmed cell death. Pyroptosis is activated by inflammasomes, leads to the release of interleukin-1 (IL-1) family cytokines, and thereby activates inflammation. In addition, inhibitors of potentially pro-inflammatory proteases and enzymes removing danger-associated cytoplasmic DNA are expressed in differentiated keratinocytes. We propose the concept of cornification as an inherently hazardous process in which damaging side effects are actively suppressed by protective mechanisms. In support of this hypothesis, loss-of-function mutations in epidermal protease inhibitors and IL-1 family antagonists suffice to induce autoinflammation. Similarly, exogenous disturbances of either cornification or its accompanying control mechanisms may be starting points for skin inflammation. Further studies into the relationship between cornification, pyroptosis and other forms of cell death will help to define the initiation phase of inflammatory skin diseases and offer new targets for disease prevention and therapy.

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NOD‐Like Receptors

Arnold

Kienes

Sowa

et al. 2018

Encyclopedia of Life Sciences

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NOD‐like receptors (NLRs) are a family of pattern recognition receptors (PRRs), able to respond to conserved microbial structures and endogenous danger signals. NLRs modulate the inflammatory response via multiple pathways including NFκB (nuclear factor kappa‐light chain‐enhancer of activated B cells)‐activation, MAPKs, ERK and inflammasome formation, which results in IL‐1β release. They act in synergy with other PRRs, bridging innate to adaptive immunity. Moreover, some NLRs directly modulate adaptive immunity via transcriptional regulation of MHC (major histocompatibility complex) class I and class II. Their essential role in orchestrating inflammatory responses is seen via their association with morbidity. NLR dysfunction can result in cancer and autoinflammatory diseases, such as Crohn's disease and ulcerative colitis, pointing out their important role in maintaining gut homeostasis. Key Concepts NLRs are an intracellular subclass of PRRs that recognise microbe‐associated molecular patterns (MAMPs) and danger‐associated molecular patterns (DAMPs). NLRs are found in different animal species and have homologues in plants. NLRs share a common tripartite structure, typically consisting of an N ‐terminal domain from the death‐fold family, a central NACHT domain and a variable number of C ‐terminal LRRs. Activation of NLRs primes innate and adaptive immunity and drives the expression of MHC class I and class II genes. Some NLRs form inflammasomes, multiprotein platforms for caspase‐1 activation and IL‐1β release. NLRs maintain gut homeostasis, differentiating between commensals and pathogens. Mutations in NLRs can lead to severe autoinflammatory diseases, cancer, dysregulation of gut homeostasis and innate immune responses. Evidence suggests that some NLRs are further implicated in development. The function of some of the 22 human NLR proteins remains elusive.

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Epidermal NLRP10 contributes to contact hypersensitivity responses in mice

Cited by 27 publications

References 34 publications

Characterization of Innate and Adaptive Immune Responses in PYNOD-Deficient Mice

Characterization of Innate and Adaptive Immune Responses in PYNOD-Deficient Mice

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

NOD‐Like Receptors

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