Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis

Murakami, Yousuke; Akahoshi, Tohru; Aoki, Naoko; Toyomoto, Masayasu; Miyasaka, Nobuyuki; Kohsaka, Hitoshi

doi:10.1002/art.24554

Cited by 64 publications

(53 citation statements)

References 44 publications

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“…64 Finally, a recent study also found a TREM-1 upregulation in peripheral blood cells from patients suffering from spondylarthropathy. 65 Thus, while TREM-1 role in acute inflammation, especially during sepsis, is today better understood, its function during chronic rheumatic diseases only begins to be elicited.…”

Section: Effects Of the Trem-1 Pathway Modulation During Inflammatorymentioning

confidence: 90%

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

Derive¹,

Massin

Gibot³

2010

Self/Nonself

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Section: Effects Of the Trem-1 Pathway Modulation During Inflammatorymentioning

confidence: 90%

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

Derive¹,

Massin

Gibot³

2010

Self/Nonself

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“…Quantitative real-time PCRs for IL-6, TNF-a, IRAK1, and GAPDH were carried out as previously described (21,22). A p16 INK4a gene-specific primer set was purchased from Qiagen (Tokyo, Japan).…”

Section: Quantification Of Cytokine and Irak1 Expressionmentioning

confidence: 99%

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Murakami

Mizoguchi

Saito

et al. 2012

The Journal of Immunology

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Induction of cyclin-dependent kinase (CDK) inhibitor gene p16INK4a into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16INK4a also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16INK4a modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16INK4a suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16INK4a gene transfer accelerated LPS-triggered IL-1R–associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16INK4a-induced IL-6 suppression. Senescent macrophages with physiological expression of p16INK4a upregulated IL-6 production when p16INK4a was targeted by specific small interfering RNA. These findings indicate that p16INK4a promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16INK4a senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.

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“…1A) [13, 15, 23–24]. While the natural TREM-1 ligand is not yet known, based on a new model of immune signaling, the signaling chain homooligomerization (SCHOOL) model [25], we have developed a novel, ligand-independent approach to TREM-1 inhibition (Fig.…”

Section: Introductionmentioning

confidence: 99%

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

Sigalov

2014

International Immunopharmacology

100

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Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the inflammatory response and plays a role in cancer and sepsis. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages suppresses cancer cell invasion in vitro. In the clinical setting, high levels of TREM-1 expression on tumor-associated macrophages are associated with cancer recurrence and poor survival of patients with non-small cell lung cancer (NSCLC). TREM-1 upregulation on peritoneal neutrophils has been found in human sepsis patients and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. In this study, we used the signaling chain homooligomerization (SCHOOL) model of immune signaling to design a novel, ligand-independent peptide-based TREM-1 inhibitor and demonstrated that this peptide specifically silences TREM-1 signaling in vitro and in vivo. Utilizing two human lung tumor xenograft nude mouse models (H292 and A549) and mice with LPS-induced sepsis, we show for the first time that blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) delays tumor growth in xenograft models of human NSCLC, 2) prolongs survival of mice with LPS-induced septic shock, and 3) substantially decreases cytokine production in vitro and in vivo. In addition, targeted delivery of SCHOOL peptides to macrophages utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis and NSCLC and possibly other types of inflammation-associated disorders.

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Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis

Abstract: Conclusion. TREM-1 ligation contributes to the pathology of autoimmune arthritis. The results of this study implied that blockade of TREM-1 could be a new approach to rheumatic diseases that is safer than the presently available immunosuppressive treatments.

Cited by 64 publications

References 44 publications

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

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