Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis

Abstract Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death rel...

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Autores principales:	Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Noriko Sakaguchi, Shimon Sakaguchi, Gen Kondoh, Akio Morinobu, Tsuneyo Mimori, Keiji Hirota
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cb03ee5c22bb4c15b64ef71023e4d277
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spelling	oai:doaj.org-article:cb03ee5c22bb4c15b64ef71023e4d2772021-12-02T17:26:48ZDispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis10.1038/s41598-021-98145-y2045-2322https://doaj.org/article/cb03ee5c22bb4c15b64ef71023e4d2772021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98145-yhttps://doaj.org/toc/2045-2322Abstract Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)—key molecules of pyroptosis and necroptosis, respectively—are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd −/−, Ripk3 −/−, or Gsdmd −/− Ripk3 −/− SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd −/− or Ripk3 −/− bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways.Yusuke TakeuchiDaiya OharaHitomi WatanabeNoriko SakaguchiShimon SakaguchiGen KondohAkio MorinobuTsuneyo MimoriKeiji HirotaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yusuke Takeuchi Daiya Ohara Hitomi Watanabe Noriko Sakaguchi Shimon Sakaguchi Gen Kondoh Akio Morinobu Tsuneyo Mimori Keiji Hirota Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
description	Abstract Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)—key molecules of pyroptosis and necroptosis, respectively—are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd −/−, Ripk3 −/−, or Gsdmd −/− Ripk3 −/− SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd −/− or Ripk3 −/− bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways.
format	article
author	Yusuke Takeuchi Daiya Ohara Hitomi Watanabe Noriko Sakaguchi Shimon Sakaguchi Gen Kondoh Akio Morinobu Tsuneyo Mimori Keiji Hirota
author_facet	Yusuke Takeuchi Daiya Ohara Hitomi Watanabe Noriko Sakaguchi Shimon Sakaguchi Gen Kondoh Akio Morinobu Tsuneyo Mimori Keiji Hirota
author_sort	Yusuke Takeuchi
title	Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
title_short	Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
title_full	Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
title_fullStr	Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
title_full_unstemmed	Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis
title_sort	dispensable roles of gsdmd and ripk3 in sustaining il-1β production and chronic inflammation in th17-mediated autoimmune arthritis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cb03ee5c22bb4c15b64ef71023e4d277
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Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis

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