TREM-1 inhibition attenuates inflammation and tumor within the colon

Zhou, Jiangang; Chai, Feng; Lu, GX; Hang, Guoping; Chen, Cheng; Chen, Xiao; Shi, Jun

doi:10.1016/j.intimp.2013.06.009

Cited by 39 publications

(36 citation statements)

References 22 publications

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“…Sequences of the specific primers are listed in Table S1. The designed specific primers were described previously (30,(36)(37)(38)(39)(40)(41). Gene expression was normalized to the GAPDH expression by calculating the Δ Ct = (Ct of GAPDH − Ct of the gene).…”

Section: Methodsmentioning

confidence: 99%

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Tokumasu

Yamaga

Yamazaki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

116

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Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1. Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.claudin-1 | tight junctions | atopic dermatitis

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Section: Methodsmentioning

confidence: 99%

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Tokumasu

Yamaga

Yamazaki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

116

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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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“…We did not detect differences in activation of caspase-1 and caspase-11 in TREM-1 knock-out macrophages suggesting that TREM-1 may not contribute to pyroptosis (38). Interestingly, recent studies have shown that TREM-1 is expressed in tumor-associated macrophages in colon, lung, and liver cancer and that the levels of TREM-1 expression correlate with the aggressiveness of tumor (19,21,22). The mechanisms by which TREM-1 contributes to tumor progression are not defined.…”

Section: Discussionmentioning

confidence: 52%

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

Yuan

Syed

Panchal

et al. 2014

Journal of Biological Chemistry

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TREM-1 inhibition attenuates inflammation and tumor within the colon

Cited by 39 publications

References 22 publications

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

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

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

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