Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

Croasdell, Amanda; Sime, Patricia J.; Phipps, Richard P.

doi:10.1096/fj.201600375r

Cited by 29 publications

(22 citation statements)

References 65 publications

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“…Not surprisingly, LPS is a potent stimulus for enhanced TLR4 expression, whereas proresolving mediators such as RvD2 suppress TLR4 expression, preventing sustained inflammatory responses. 52 Both up-and downregulation of TLR4 involve microRNAs, including inhibitory miR146a. 53 Whether miRNAmediated modulation of the expression of TLR4, along with MD2, is involved in fibrosis and SSc, has not been explored.…”

Section: Multiple Mechanisms To Prevent Aberrant Tlr4 Activationmentioning

confidence: 99%

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

Bhattacharyya

Midwood

Yin

et al. 2017

Advances in Wound Care

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Section: Multiple Mechanisms To Prevent Aberrant Tlr4 Activationmentioning

confidence: 99%

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

Bhattacharyya

Midwood

Yin

et al. 2017

Advances in Wound Care

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“…17,18 These are derivatives of omega-3 fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and the lipoxins. 17,[19][20][21][22][23][24][25][26][27] These novel compounds have demonstrated safety and efficacy as HMTs and function by preventing the destructive prolongation, or chronicity, of the inflammatory response, but do not block its acute phase which is necessary to combat infections. 9,28,29 However, none of these formulations has been governmentapproved as therapeutic agents for periodontitis at this time.…”

Section: Introductionmentioning

confidence: 99%

<p>Chemically-Modified Curcumin 2.24: A Novel Systemic Therapy for Natural Periodontitis in Dogs</p>

Golub¹,

Lee²,

Lin³

et al. 2020

JEP

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Purpose:To determine the effect of a pleiotropic MMP-inhibitor, a novel chemicallymodified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturallyoccurring periodontitis in the beagle dog. Methods: Eight adult female dogs with generalized periodontitis were distributed into two groups: Placebo and Treatment (n=4/group). After a 1-hr full-mouth scaling and root planing (SRP) at time 0, placebo or CMC2.24 (10mg/kg) capsules were orally administered once/day for 3 months. Various clinical periodontal parameters (e.g., pocket depth, gingival index) were measured at different time periods (0, 1, 2 and 3 months), and gingival crevicular fluid (GCF) samples and gingival tissue biopsies (3-month) were analyzed for cytokines, MMPs and cell-signaling molecules. Standardized radiographs were taken at 0 and 3-month; in addition, peripheral blood monocytes/macrophages from these dogs at 3-month were cultured and analyzed for the pro-, activated-, and total-forms of both MMP-2 and MMP-9. Results: CMC2.24 treatment significantly reduced gingival inflammation (gingival index, GCF flow), pocket depth (PD), and the numbers of pockets (PD≥4mm), compared to placebo. CMC2.24 also significantly reduced MMP-9 and MMP-2 (primarily in the activated-form) in gingival tissue, alveolar bone loss, and reduced GCF IL-1β. Cell-signaling molecules, TLR-2 (but not TLR-4) and p38 MAPK, responded to CMC2.24 in a pattern consistent with reductions in inflammation and collagenolysis. In culture, CMC2.24 had no effect on pro-MMP-9 but essentially completely blocked the conversion of pro-to activated-MMP-9 in systemic blood-derived monocytes/macrophages from these dogs. Conclusion: In the beagle dog model of natural periodontitis, orally administered CMC2.24 (a novel triketonic phenylaminocarbonyl-curcumin) significantly decreased clinical measures of periodontitis as well as pro-inflammatory cytokines, MMPs, and cell-signaling molecules. These and previous studies, using other in vitro and in vivo models, support the clinical potential of CMC2.24 as a novel adjunct to SRP in the treatment of chronic periodontitis.

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“…Among the SPM family, in the current study, we focused our attention on resolvins of the D‐series and in particular in resolvin (Rv) D1 and RvD2, which are the most widely characterized and their receptors have been identified and cloned . In addition, these SPMs potently reduce the secretion of proinflammatory cytokines by activated macrophages, and more specifically are capable of reducing the expression of IL‐1β at the mRNA level in THP‐1 monocytic cells, burn wound neutrophils , and vascular smooth muscle cells as well as to reduce the levels of mature IL‐1β protein in adipose tissue, liver, and THP‐1 macrophages . However, the molecular determinants underlying the modulatory actions of these SPMs on IL‐1β levels have not yet been characterized.…”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome

Lopategi

Flores‐Costa

Rius

et al. 2018

Journal of Leukocyte Biology

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The prototypic proinflammatory cytokine IL-1β plays a central role in innate immunity and inflammatory disorders. The formation of mature IL-1β from an inactive pro-IL-1β precursor is produced via nonconventional multiprotein complexes called the inflammasomes, of which the most common is the nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome composed by NLRP3, (ASC) apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD), and caspase-1. Specialized proresolving mediators (SPMs) promote resolution of inflammation, which is an essential process to maintain host health. SPMs prevent excessive inflammation by terminating the inflammatory response and returning to tissue homeostasis without immunosupression. This study tested the hypothesis that modulation of the NLRP3 inflammasome in macrophages is one mechanism involved in the SPM-regulated processes during resolution. Our findings demonstrate that the SPM resolvin D2 (RvD2) suppressed the expression of pro-IL-1β and reduced the secretion of mature IL-1β in bone marrow-derived macrophages challenged with LPS+ATP (classical NLRP3 inflammasome model) or LPS+palmitate (lipotoxic model). Similar findings were observed in thioglycolate-elicited peritoneal macrophages, in which RvD2 remarkably reduced ASC oligomerization, inflammasome assembly, and caspase-1 activity. In vivo, in a self-resolving zymosan A-induced peritonitis model, RvD2 blocked the NLRP3 inflammasome leading to reduced release of IL-1β into the exudates, repression of osteopontin, and MCP-1 expression and induction of M2 markers of resolution (i.e., CD206 and arginase-1) in peritoneal macrophages. RvD2 inhibitory actions were receptor mediated and were abrogated by a selective GPR18 antagonist. Together, these findings support the hypothesis that SPMs have the ability to inhibit the priming and to expedite the deactivation of the NLRP3 inflammasome in macrophages during the resolution process.

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Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

Cited by 29 publications

References 65 publications

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

<p>Chemically-Modified Curcumin 2.24: A Novel Systemic Therapy for Natural Periodontitis in Dogs</p>

Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome

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