TNF, but Not IL-6 and IL-17, Is Crucial for the Development of T Cell-Independent Psoriasis-Like Dermatitis in <i>Il1rn</i>−/− Mice

Nakajima, Ayako; Matsuki, Taizo; Komine, Mayumi; Asahina, Akihiko; Horai, Reiko; Nakae, Susumu; Ishigame, Harumichi; Kakuta, Shigeru; Saijo, Shinobu; Iwakura, Yoichiro

doi:10.4049/jimmunol.1001227

Cited by 43 publications

(31 citation statements)

References 60 publications

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“…Moreover, the researchers demonstrate that this psoriasis-like disease developed in a TNF-α dependent manner [79]. Interestingly, this psoriasis-like disease also occurred in IL - 1rn –/– SCID mice [80]. Consequently, such data suggested that T lymphocytes are not essential for the development of psoriasis.…”

Section: Resultsmentioning

confidence: 99%

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

2018

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Background: Psoriasis is a common, chronic inflammatory skin disorder, which can significantly impact quality of life. Despite major breakthroughs in our understanding of the pathogenesis of psoriasis, the chronological order of the underlying mechanisms leading to the development of psoriatic plaques remains to be completely understood. Summary: Although psoriasis is classically perceived as a T-cell disease, it is now well recognized that T lymphocytes do not function in exclusivity. This theory is supported by evidence from transgenic murine models that develop marked psoriasiform disease. In addition, immune cells and cytokines regulate both early and late events involved in the pathogenesis of psoriasis. Key Messages: Psoriasis is a complex disease – a dynamic interplay between immune cells, keratinocytes, and various other skin-resident cells, such as endothelial and immune cells. The contribution of each cell type is crucial in the initiation and maintenance phases of psoriatic alterations.

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Section: Resultsmentioning

confidence: 99%

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

2018

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“…Constitutive IL-1β activation or the lack of the IL-1 receptor antagonist in mice leads to a T H 17 cytokine profile in skin and an inflammatory phenotype resembling human psoriasis (5, 6). Moreover, excess IL-1 signaling causes psoriasis-like skin disease in mice even in the absence of T cells (7). …”

Section: Introductionmentioning

confidence: 99%

Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic Lesions

et al. 2011

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The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.

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“…Conversely, BALB/c mice lacking IL-1Ra, which is encoded by the gene, IL-1RN , spontaneously develop arthritis and a psoriasis-like skin disorder 18–21. The consequences of dysregulated IL-1 signalling on the eye, however, have yet to be examined in IL-1Ra knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

Impact of IL-1 signalling on experimental uveitis and arthritis

Planck

Woods

Clowers

et al. 2012

Annals of the Rheumatic Diseases

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Background Uveitis, or inflammatory eye disease, is a common extra-articular manifestation of many systemic autoinflammatory diseases involving the joints. Anakinra (recombinant interleukin (IL)-1 receptor antagonist (Ra)) is an effective therapy in several arthritic diseases; yet, few studies have investigated the extent to which IL-1 signalling or IL-1Ra influences the onset and/or severity of uveitis. Objective To seek possible links between arthritis and uveitis pathogenesis related to IL-1 signalling. Methods The eyes of IL-1Ra-deficient BALB/c mice were monitored histologically and by intravital videomicroscopy to determine if uveitis developed along with the expected spontaneous arthritis in ankles and knees. Expression levels of IL-1R and its negative regulators (IL-1Ra, IL-1RII, IL-1RAcP and single Ig IL-1R-related molecule) in eye and joint tissues were compared. Differences in uveitis induced by intraocular injection of lipopolysaccharide (LPS) in mice lacking IL-1R or IL-1Ra were assessed. Results Deficiency in IL-1Ra predisposes to spontaneous arthritis, which is exacerbated by previous systemic LPS exposure. The eye, however, does not develop inflammatory disease despite the progressive arthritis or LPS exposure. Organ-specific expression patterns for IL-1Ra and negative regulators of IL-1 activity were observed that appear to predict predisposition to inflammation in each location in IL-1Ra knockout mice. The eye is extremely sensitive to locally administered LPS, and IL-1Ra deficiency markedly exacerbates the resulting uveitis. Conclusion This study demonstrates that IL-1Ra plays an important role in suppressing local responses in eyes injected with LPS and that there is discordance between murine eyes and joints in the extent to which IL-1Ra protects against spontaneous inflammation.

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TNF, but Not IL-6 and IL-17, Is Crucial for the Development of T Cell-Independent Psoriasis-Like Dermatitis in Il1rn−/− Mice

Cited by 43 publications

References 60 publications

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic Lesions

Impact of IL-1 signalling on experimental uveitis and arthritis

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