Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis

Denning, Naomi-Liza; Aziz, Monowar; Murao, Atsushi; Gurien, Steven D.; Ochani, Mahendar; Prince, José M.; Wang, Haichao

doi:10.1172/jci.insight.134172

Cited by 99 publications

(158 citation statements)

References 47 publications

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“…Although several TREM-1 antagonists are available, most of them were developed and designed from the extracellular TREM-1 sequence and serve as TREM-1 decoy receptors. [48] M3 was developed from eCIRP's sequence to speci cally abrogate the eCIRP/TREM-1 ligand/receptor interaction [26], while allowing other molecules that regulate in ammation to be un-interrupted.…”

Section: Discussionmentioning

confidence: 99%

“…at the time of cecal slurry injection. [26] For the survival study, an additional group of mice received M3 2 h after CS injection.…”

Section: In Vivo Administration Of Rmcirp and M3mentioning

confidence: 99%

“…[25] We have recently shown that eCIRP is a ligand of TREM-1. [26] TREM-1 is an activating, proin ammatory receptor, propagating in ammation independently [27], as well as synergistically with the toll-like receptor 4 (TLR4) pathway. [27,28] Both eCIRP and TREM-1 are upregulated in sepsis to serve as mediators of in ammation.…”

Section: Introductionmentioning

confidence: 99%

“…[27,28] Both eCIRP and TREM-1 are upregulated in sepsis to serve as mediators of in ammation. [19,26] We recently developed a small eCIRP-derived peptide (RGFFRGG), named M3, that is an antagonist of the eCIRP/TREM-1 interaction. We successfully implemented M3 as a therapeutic agent in adult murine models of sepsis.…”

Section: Introductionmentioning

confidence: 99%

“…We successfully implemented M3 as a therapeutic agent in adult murine models of sepsis. [26] However, the neonatal immune response is dramatically different than its adult counterpart. [29] Neonates rely almost exclusively on innate immunity yet have a relatively downregulated NF-κΒ pathway compared to adults.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the eCIRP/TREM-1 Interaction with a Small Molecule Inhibitor Improves Cardiac Dysfunction in Neonatal Sepsis

Denning

Aziz

et al. 2020

Preprint

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Background: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. Methods: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. Results: Serum CIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. Conclusions: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration: Retrospectively registered.

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Section: Discussionmentioning

confidence: 99%

“…at the time of cecal slurry injection. [26] For the survival study, an additional group of mice received M3 2 h after CS injection.…”

Section: In Vivo Administration Of Rmcirp and M3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the eCIRP/TREM-1 Interaction with a Small Molecule Inhibitor Improves Cardiac Dysfunction in Neonatal Sepsis

Denning

Aziz

et al. 2020

Preprint

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Frontline Science: Extracellular CIRP generates a proinflammatory Ly6G+CD11bhi subset of low-density neutrophils in sepsis

Takizawa

Murao

Ochani

et al. 2020

Journal of Leukocyte Biology

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Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern. Neutrophils present in the mononuclear cell fraction of Ficoll gradient separation are called low-density neutrophils (LDNs). Here we report the novel role of eCIRP on LDNs' heterogeneity in sepsis. Sepsis was induced in male C57BL/6 wild-type (WT) and CIRP −/− mice by cecal ligation and puncture (CLP). At 20 h after CLP, LDNs in the blood were isolated by Ficoll gradient separation, followed by staining the cells with anti-Ly6G and anti-CD11b Abs and detection by flow cytometry. Sepsis or recombinant murine CIRP (rmCIRP) injection in mice resulted in significant increase in the frequency (%) and number of Ly6G + CD11b hi and Ly6G + CD11b lo LDNs in the blood compared to sham-or vehicle-treated mice. At 20 h of CLP, CIRP −/− mice had significantly lower frequency and number of Ly6G + CD11b hi and Ly6G + CD11b lo LDNs in the blood compared to WT mice. In sepsis mice or rmCIRP-injected mice, compared to Ly6G + CD11b lo LDNs, the expression of CXCR4, ICAM-1, and iNOS and formation of reactive oxygen species, and neutrophil extracellular traps in Ly6G + CD11b hi LDNs in the blood were significantly increased. Treatment of WT bone marrow-derived neutrophils (BMDNs) with rmCIRP increased Ly6G + CD11b hi LDN frequency, whereas treatment of TLR4 −/− BMDNs with rmCIRP significantly decreased the frequency of Ly6G + CD11b hi LDNs. BMDNs' stimulation with rmCIRP increased the expression of transcription factors in LDNs. eCIRP induces the formation of a proinflammatory phenotype Ly6G + CD11b hi of LDNs through TLR4. Targeting eCIRP may provide beneficial outcomes in sepsis by decreasing proinflammatory Ly6G + CD11b hi LDNs.

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The vitals of NETs

Tan

Aziz

Wang

2020

Journal of Leukocyte Biology

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119

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Neutrophils produce neutrophil extracellular traps (NETs) by expelling their extracellular chromatin embedded with citrullinated histone H3, myeloperoxidase, and other intracellular molecules. Since their discovery in 2004, numerous articles have demonstrated the mechanism of NET formation and their function in innate immunity and inflammation. NET components often play an antimicrobial role, but excessive NETs are deleterious and can cause inflammation and tissue damage. This review highlights recent advancements in the identification of novel pathways and mechanisms of NET formation. We also focus on the specific damaging impact of NETs in individual organs. We then discuss the progress and limitations of various NET detection assays. Collectively, these vital aspects of NETs significantly improve our understanding of the pathobiology of NETs and future diagnostics and therapeutic tools for examining and modulating NETs in inflammatory diseases.

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Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis

Abstract: PW is an inventor of patent applications (WO/2010/120726 and 61/881.798) covering the fundamental concept of targeting cold-inducible RNAbinding protein for the treatment of inflammatory diseases, licensed by TheraSource LLC. PW is a cofounder of TheraSource LLC.

Cited by 99 publications

References 47 publications

Targeting the eCIRP/TREM-1 Interaction with a Small Molecule Inhibitor Improves Cardiac Dysfunction in Neonatal Sepsis

Targeting the eCIRP/TREM-1 Interaction with a Small Molecule Inhibitor Improves Cardiac Dysfunction in Neonatal Sepsis

Frontline Science: Extracellular CIRP generates a proinflammatory Ly6G+CD11bhi subset of low-density neutrophils in sepsis

The vitals of NETs

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