1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin...

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Autores principales:	Takahisa Nakajo, Takeshi Katayoshi, Natsuko Kitajima, Kentaro Tsuji-Naito
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Vitamin D Inflammasome IL-1β Reactive oxygen species NRF2-HO-1 pathway Normal human epidermal keratinocytes Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b0c8af0843d04c388ac6b05c5d30dfb8
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spelling	oai:doaj.org-article:b0c8af0843d04c388ac6b05c5d30dfb82021-12-04T04:34:05Z1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes2213-231710.1016/j.redox.2021.102203https://doaj.org/article/b0c8af0843d04c388ac6b05c5d30dfb82021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003633https://doaj.org/toc/2213-2317The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH)2VD3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH)2VD3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH)2VD3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH)2VD3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH)2VD3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH)2VD3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH)2VD3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K+ efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH)2VD3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH)2VD3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH)2VD3 on IL-1β secretion. Our results indicate that 1,25(OH)2VD3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH)2VD3, which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH)2VD3 as a therapeutic agent for inflammasome-related skin diseases.Takahisa NakajoTakeshi KatayoshiNatsuko KitajimaKentaro Tsuji-NaitoElsevierarticleVitamin DInflammasomeIL-1βReactive oxygen speciesNRF2-HO-1 pathwayNormal human epidermal keratinocytesMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102203- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Vitamin D Inflammasome IL-1β Reactive oxygen species NRF2-HO-1 pathway Normal human epidermal keratinocytes Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Vitamin D Inflammasome IL-1β Reactive oxygen species NRF2-HO-1 pathway Normal human epidermal keratinocytes Medicine (General) R5-920 Biology (General) QH301-705.5 Takahisa Nakajo Takeshi Katayoshi Natsuko Kitajima Kentaro Tsuji-Naito 1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
description	The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH)2VD3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH)2VD3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH)2VD3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH)2VD3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH)2VD3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH)2VD3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH)2VD3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K+ efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH)2VD3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH)2VD3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH)2VD3 on IL-1β secretion. Our results indicate that 1,25(OH)2VD3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH)2VD3, which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH)2VD3 as a therapeutic agent for inflammasome-related skin diseases.
format	article
author	Takahisa Nakajo Takeshi Katayoshi Natsuko Kitajima Kentaro Tsuji-Naito
author_facet	Takahisa Nakajo Takeshi Katayoshi Natsuko Kitajima Kentaro Tsuji-Naito
author_sort	Takahisa Nakajo
title	1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
title_short	1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
title_full	1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
title_fullStr	1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
title_full_unstemmed	1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes
title_sort	1,25-dihydroxyvitamin d3 attenuates il-1β secretion by suppressing nlrp1 inflammasome activation by upregulating the nrf2-ho-1 pathway in epidermal keratinocytes
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b0c8af0843d04c388ac6b05c5d30dfb8
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1,25-Dihydroxyvitamin D3 attenuates IL-1β secretion by suppressing NLRP1 inflammasome activation by upregulating the NRF2-HO-1 pathway in epidermal keratinocytes

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