A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs

Li, Yan; Cao, Hongwei; Wang, Ning; Xiang, Yang; Lu, Yong; Zhao, Kecen; Zheng, Jie; Zhou, Hong

doi:10.1016/j.vaccine.2010.10.042

Cited by 13 publications

(10 citation statements)

References 23 publications

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“…More recent studies have found that many CpG-ODNs do not have immunostimulatory properties; in fact, only some CpG-ODNs block the activation of TLR9 [18,36]. As we previously reported, CpG-c41, which we screened from a large collection of 7 Mediators of Inflammation nonimmunostimulatory CpG-ODNs, has a special sequence structure and an outstanding capacity to suppress TLR9 activation [22]. In this study, we discovered additional evidence that CpG-c41 has multiple immunosuppressive effects.…”

Section: Discussionsupporting

confidence: 52%

“…Immunosuppressive Effects of CpG-c41. TLR9 specifically recognizes CpG-ODNs, and the nonstimulatory CpG-c41 molecule was previously known only as a TLR9 antagonist [22]. Therefore, we investigated if the immunosuppressive effects of CpG-c41 on cytokine secretion downstream of other TLRs were related to TLR9-mediated crosstalk.…”

Section: Tlr9-independentmentioning

confidence: 99%

“…Here, we report new findings on a nonstimulatory CpGcontaining oligodeoxynucleotide (CpG-ODN), previously known only as a TLR9 antagonist, CpG-c41 [22]. We present multiple immunosuppressive effects of CpG-c41 on intracellular TLR-mediated activity.…”

Section: Introductionmentioning

confidence: 96%

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Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

Liu

Yang

Wang

et al. 2017

Mediators of Inflammation

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A growing body of literature suggests that most chronic autoimmune diseases are associated with inappropriate inflammation mediated by Toll-like receptor (TLR) 3, TLR7/8, or TLR9. Therefore, research into blocking TLR activation to treat these disorders has become a hot topic. Here, we report the immunomodulatory properties of a nonstimulatory CpG-containing oligodeoxynucleotide (CpG-ODN), CpG-c41, which had previously only been known as a TLR9 antagonist. In this study, we found that both in vitro and in vivo CpG-c41 decreased levels of various proinflammatory factors that were induced by single activation or coactivation of intracellular TLRs, but not membrane-bound TLRs, no matter what downstream signal pathways the TLRs depend on. Moreover, CpG-c41 attenuated excessive inflammation in the imiquimod-induced psoriasis-like mouse model of skin inflammation by suppressing immune cell infiltration and release of inflammatory factors. We also found evidence that the immunosuppressive effects of CpG-c41 on other intracellular TLRs are mediated by a TLR9-independent mechanism. These results suggest that CpG-c41 acts as an upstream of signaling cascades, perhaps on the processes of ligand internalization and transfer. Taken together, these results suggest that CpG-c41 disrupts various aspects of intracellular TLR activation and provides a deeper insight into the regulation of innate immunity.

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Section: Discussionsupporting

confidence: 52%

Section: Tlr9-independentmentioning

confidence: 99%

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Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

Liu

Yang

Wang

et al. 2017

Mediators of Inflammation

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“…TLR9 is a receptor that senses bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). The extracellular domain (ECD) of human TLR9 (hTLR9) comprises 25 leucine-rich repeats (LRR) that contribute to binding of CpG ODN [ 2 , 3 ]. Internalized CpG ODN within the endosome initiates TLR9-mediated signaling via sequential recruitment of MyD88, interleukin receptor associated kinase (IRAK) and TNF-α receptor associated factor 6 (TRAF6), which in turn activate important downstream transcription factors, such as NF-κB and AP-1, culminating in the induction of proinflammatory cytokines such as TNF-α and IL-6 [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Various TLRs and their adapter proteins have many universal molecules; therefore, MyD88-target inhibitors can destroy the immune system [ 8 ]. In addition, we investigated an inhibitory CpG ODN designed as a TLR9 antagonist to block immunostimulatory CpG ODN to treat sepsis and lupus nephritis [ 2 ]. However, its application was limited because of its low target-specificity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides

Pan

Kuang

et al. 2016

IJMS

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Toll-like receptor (TLR) 9 is an endosomal receptor recognizing bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). Blocking CpG ODN/TLR9 activity represents a strategy for therapeutic prevention of immune system overactivation. Herein, we report that a synthetic peptide (SP) representing the leucine-rich repeat 11 subdomain of the human TLR9 extracellular domain could attenuate CpG ODN/TLR9 activity in RAW264.7 cells by binding to CpG ODN and decreasing its internalization. Our results demonstrate that preincubation with SP specifically inhibited CpG ODN- but not lipopolysaccharide (LPS)- and lipopeptide (PAM3CSK4)-stimulated TNF-α and IL-6 release. Preincubation of SP with CpG ODN dose-dependently decreased TLR9-driven phosphorylation of IκBα and ERK and activation of NF-κB/p65. Moreover, SP dose-dependently decreased FAM-labeled CpG ODN internalization, whereas non-labeled CpG ODN reversed the inhibition. The KD value of SP-CpG ODN binding was within the micromolar range. Our results demonstrated that SP was a specific inhibitor of CpG ODN/TLR9 activity via binding to CpG ODN, leading to reduced ODN internalization and decreased activation of subsequent pathways within cells. Thus, SP could be used as a potential CpG ODN antagonist to block TLR9 signaling.

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Toll-Like Receptors (TLRs) as Therapeutic Targets for Treating SARS-CoV-2: An Immunobiological Perspective

Patra

Das

Mukherjee

2021

Coronavirus Therapeutics – Volume I

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A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs

Cited by 13 publications

References 23 publications

Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides

Toll-Like Receptors (TLRs) as Therapeutic Targets for Treating SARS-CoV-2: An Immunobiological Perspective

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