Aldose reductase mediates NLRP3 inflammasome-initiated innate immune response in hyperglycemia-induced thp1 monocytes and male mice

Pabitra B. Pal, Himangshu Sonowal, Kirtikar Shukla, Satish Srivastava, Kota Ramana

Research output: Contribution to journalArticle

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Abstract

Despite recent studies that show oxidative stress-generated reactive oxygen species (ROS) regulate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated innate immune response in various diabetic complications, the mechanism by which ROS activate innate immune response is not well understood. We have shown previously that aldose reductase (AR), besides reducing glucose, reduces lipid aldehydes and their glutathione conjugates and participates in various oxidative stress-induced inflammatory pathways. To understand the role of AR in ROSinduced innate immune response, we have investigated the mechanism(s) by which AR activates hyperglycemia-induced NLRP3 inflammsome-initiated innate immune response in Thp1 monocytes and in streptozotocin (STZ)-induced diabetic mice. In Thp1 monocytes, inhibition or ablation of AR prevented high-glucose-induced activation of NLRP3 inflammasome and caspase-1 and release of the innate immune cytokines interleukin (IL)-1b and IL-18. AR inhibition in Thp1 cells also prevented the high-glucose-induced generation of ROS, influx of Ca2+, efflux of K+, and activation of Lyn, Syk, and PI3K. Furthermore, the AR inhibitor fidarestat prevented the expression of NLRP inflammasome components in STZ-induced diabetic mouse heart and aorta, and also prevented the release of various cytokines in the serum. Collectively, our data suggest that AR regulates hyperglycemiainduced NLRP3 inflammasome-mediated innate immune response by altering the ROS/Lyn/Syk/ PI3K/Ca2+/K+ signals.

Original languageEnglish (US)
Pages (from-to)3661-3675
Number of pages15
JournalEndocrinology
Volume158
Issue number10
DOIs
StatePublished - Oct 1 2017

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Inflammasomes
Aldehyde Reductase
Innate Immunity
Hyperglycemia
Monocytes
Reactive Oxygen Species
Streptozocin
Phosphatidylinositol 3-Kinases
Glucose
Oxidative Stress
Cytokines
Caspase 1
Interleukin-18
Interleukins
Diabetes Complications
Pyrin Domain
NLR Proteins
Aldehydes
Glutathione
Aorta

ASJC Scopus subject areas

  • Endocrinology

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Aldose reductase mediates NLRP3 inflammasome-initiated innate immune response in hyperglycemia-induced thp1 monocytes and male mice. / Pal, Pabitra B.; Sonowal, Himangshu; Shukla, Kirtikar; Srivastava, Satish; Ramana, Kota.

In: Endocrinology, Vol. 158, No. 10, 01.10.2017, p. 3661-3675.

Research output: Contribution to journalArticle

Pal, Pabitra B. ; Sonowal, Himangshu ; Shukla, Kirtikar ; Srivastava, Satish ; Ramana, Kota. / Aldose reductase mediates NLRP3 inflammasome-initiated innate immune response in hyperglycemia-induced thp1 monocytes and male mice. In: Endocrinology. 2017 ; Vol. 158, No. 10. pp. 3661-3675.
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