Class A CpG Oligonucleotide Priming Rescues Mice from Septic Shock via Activation of Platelet-Activating Factor Acetylhydrolase

Yamamoto, Yuroku; Sugimura, Ryu; Watanabe, Takafumi; Shigemori, Suguru; Okajima, Takuma; Nigar, Shireen; Namai, Fu; Sato, Takashi; Ogita, Tasuku; Shimosato, Takeshi

doi:10.3389/fimmu.2017.01049

Cited by 14 publications

(13 citation statements)

References 48 publications

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“…Unlike type-B CpG sequences, the type-A CpG ODNs are poor activators of NF-κB signaling and cytokines such as IL-6 and IL-10. 40 While recent study showed that injections of CpG(A) alleviated severity of sepsis in mice by reducing blood clotting, 41 the control CpG(A)-scrRNA did not show anti-inflammatory activity in our experiments. The presence of functional miR-146a-5p guide strand in the CpG conjugate was key to the biological activity of this oligonucleotide.…”

Section: Discussioncontrasting

confidence: 59%

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

Wang

Mann

et al. 2020

Blood

103

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NF-κB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-κB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell–selective NF-κB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-κB in target cells. IV injections of C-miR146a mimic to miR-146a–deficient mice prevented excessive NF-κB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell–induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-κB–related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell–targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.

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Section: Discussioncontrasting

confidence: 59%

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

Wang

Mann

et al. 2020

Blood

103

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“…The purified total RNA was reverse-transcribed using a PrimeScript TM RT Master Mix (TaKaRa Bio Inc., Osaka, Japan) according to the manufacturer's instructions. Quantitative PCR (qPCR) reactions were performed as described previously (27). Primers for the transcripts encoding β-actin, IL-4, and IFN-γ were purchased from TaKaRa Bio, Inc.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Oral Administration of Flavonifractor plautii Strongly Suppresses Th2 Immune Responses in Mice

et al. 2020

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The bacterium Flavonifractor plautii (FP), which is found in human feces, has been reported to participate in catechin metabolism in the gut, but this bacterium's effects on immune function are unclear. We assessed the effect of oral administration of FP on the immune response in ovalbumin (OVA) -sensitized mice. We demonstrated that the FP treatment suppressed interleukin (IL)-4 in splenocytes and OVA-specific IgE production in serum from OVA-sensitized mice. Moreover, oral administration of FP augmented CD4 + CD25 + T cells and CD103 + CD11c + DCs. In animals of the FP group, the proportion of FP was increased in the mesenteric lymph nodes (MLNs), as was the proportion of Deferribacteres in the cecum. Oral administration of FP may inhibit the Th2 immune response by incorporation into the MLNs and/or by inducing changes in the gut microbiota. Thus, FP may be useful in alleviating antigen-induced Th2 immune responses.

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“…Quantitative PCR (qPCR) was performed as described previously 17,18 . Primers for five genes (encoding IFN-γ, TNF-α, IL-1β, IL-6, and IL-17) were obtained from TaKaRa Bio, Inc. Alexa Fluor ® 488 anti-mouse CD4 (CAT# 100423; BioLegend) and PerCP/Cy5.5 anti-mouse IL-17A antibodies (CAT# 506919; BioLegend) were used.…”

Section: Cytokine Assaymentioning

confidence: 99%

Microbial therapeutics for acute colitis based on genetically modified Lactococcus lactis hypersecreting IL-1Ra in mice

et al. 2020

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The increased incidence of inflammatory bowel disease (IBD) in Western and rapidly Westernizing developing countries poses a global pandemic threat. The development of affordable drugs for treating IBD worldwide is thus a priority. Genetically modified lactic acid bacteria (gmLAB) as microbial therapeutics are inexpensive protein producers suitable for use as carriers of protein to the intestinal mucosa. Here, we successfully constructed gmLAB hypersecreting interleukin 1 receptor antagonist (IL-1Ra). Oral administration of these gmLAB suppressed body weight reduction and exacerbation of the disease activity index score in mice with acute colitis and decreased the number of CD4+ IL-17A+ cells in the mesenteric lymph nodes. These data suggest that the gmLAB deliver IL-1Ra to the colon, where it inhibits IL-1 signaling. We thus developed a novel IBD therapeutic that blocks IL-1 signaling using a gmLAB protein delivery system. This system could be an inexpensive oral microbial therapeutic.

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Class A CpG Oligonucleotide Priming Rescues Mice from Septic Shock via Activation of Platelet-Activating Factor Acetylhydrolase

Cited by 14 publications

References 48 publications

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

Myeloid cell–targeted miR-146a mimic inhibits NF-κB–driven inflammation and leukemia progression in vivo

Oral Administration of Flavonifractor plautii Strongly Suppresses Th2 Immune Responses in Mice

Microbial therapeutics for acute colitis based on genetically modified Lactococcus lactis hypersecreting IL-1Ra in mice

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