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Copyright (c) 2024 Seda Kurt, Sefika Pinar Senol, Dilsah Ezgi Yilmaz, Omer Bahceli, Beyza Ozgen, Zainab Sabrie, Muhammed Ahmed-Reda Elosman, Bahar Tunctan
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.Inhibition of RIPK1-driven necroptosis ameliorates inflammatory hyperalgesia caused by lipopolysaccharide: involvement of TLR-, NLRP3-, and caspase-11-mediated signaling pathways
Corresponding Author(s) : Bahar Tunctan
Cellular and Molecular Biology,
Vol. 70 No. 12: Issue 12
Abstract
Increasing evidence suggests that inhibition of receptor-interacting serine/threonine-protein kinase (RIPK) 1/RIPK3/mixed lineage kinase domain-like pseudokinase (MLKL) necrosome has protective effects in vivo models of painful conditions seen in humans associated with inflammation and demyelination in the central nervous system. However, the contribution of RIPK1-driven necroptosis to inflammatory pain remains unknown. Therefore, this study aims to determine the effect of necrostatin (Nec) -1s, a selective RIPK1 inhibitor, on lipopolysaccharide (LPS)-induced inflammatory pain and related underlying mechanisms. In the saline-, LPS-, and/or Nec-1s-injected male mice, thermal hyperalgesia was evaluated by hot plate test. Alterations in the expression of proteins involved in the RIPK1, toll-like receptor (TLR) 4, myeloid differentiation factor (MyD) 88/toll-interleukin (IL)-1 receptor domain-containing adapter-inducing interferon-β (TRIF)/nuclear factor (NF)-kB, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing (NLRP) 3/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/pro-caspase-1, and caspase-11/gasdermin D (GSDMD) signaling pathways, as well as proteins related to demyelination and remyelination in the brain and spinal cord were determined by the immunoblotting method. The LPS-induced alleviation of thermal hyperalgesia was prevented by necrostatin-1s. Necrostatin-1s reversed (1) increased activity of RIPK1, RIPK3, MLKL, and NF-kB p65, (2) enhanced expression of TLR4, MyD88, TRIF, NF-kB p65, HMGB1, NLRP3, ASC, caspase-1 p20, IL-1β, caspase-11 p20, p30-GSDMD, and semaphorin 3A, and (3) diminished myelin PLP expression induced by LPS. These findings suggest that the use of RIPK1 inhibitors could be a therapeutic approach in the management of inflammatory pain associated with necroptosis, pyroptosis, and demyelination.
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