The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity

Ramirez-Ortiz, Zaida G.; Prasad, Amit; Griffith, Jason W.; Pendergraft, William F.; Cowley, Glenn S.; Root, David E.; Tai, Melissa; Luster, Andrew D.; Khoury, Joseph El; Hacohen, Nir; Means, Terry K.

doi:10.1038/ni.3143

Cited by 65 publications

(59 citation statements)

References 45 publications

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“…TREML4 is expressed on CD24 + cDCs, monocytes (Hemmi et al, 2012) and macrophages, where it regulates TLR7 signaling amplification (Ramirez-Ortiz et al, 2015). Ly-6C hi monocytes were heterogeneous for TREML4 expression, but Ly-6C lo monocytes were uniformly TREML4 positive (Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells

et al. 2016

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Summary Both classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs) are capable of cross-priming CD8+ T cells in response to cell-associated antigens. We found that Ly-6ChiTREML4− monocytes can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4, but that Ly-6ChiTREML4+ monocytes were committed to differentiate into Ly-6CloTREML4+ monocytes. Differentiation of Zbtb46+ Mo-DCs capable of efficient cross-priming required both GM-CSF and IL-4, and was accompanied by induction of Batf3 and Irf4. However, monocytes require IRF4, but not BATF3, to differentiate into Zbtb46+ Mo-DCs capable of cross-priming CD8+ T cells. Instead, Irf4−/− monocytes differentiate into macrophages in response to GM-CSF and IL-4. Thus, cDCs and Mo-DCs require distinct transcriptional programs of differentiation in acquiring the capacity to prime CD8+ T cells. These differences may be of consideration in the use of therapeutic DC vaccines based on Mo-DCs.

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Section: Resultsmentioning

confidence: 99%

Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells

et al. 2016

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“…Multiple PRRs work in synergy to detect viral RNA or proteins synthesized during influenza replication (46–48). A well-orchestrated host response may help to maintain the inflammatory response while inducing an effective adaptive immune response for viral clearance.…”

Section: Discussionmentioning

confidence: 99%

CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo

Teng

Chen

Hsu

et al. 2017

J Virol

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Human infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections. IMPORTANCE Multiple pattern recognition receptors work in synergy to sense viral RNA or proteins synthesized during influenza replication and mediate host responses for viral control. Well-orchestrated host responses may help to maintain the inflammatory response to minimize tissue damage while inducing an effective adaptive immune response for viral clearance. We identified that CLEC5A, a C-type lectin receptor which has previously been reported to mediate flavivirus-induced inflammatory responses, enhanced induction of proinflammatory cytokines and chemokines in myeloid cells after influenza infections. CLEC5A-deficient mice infected with influenza virus showed reduced inflammation in the lungs and improved survival compared to that of the wild-type mice despite comparable viral loads. The survival difference was more prominent at a lower dose of inoculum. Collectively, our results suggest that dampening CLEC5A-mediated inflammatory responses in myeloid cells reduces immunopathogenesis after influenza infections.

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“…At day 9, BMDCs were stimulated with 100 ng/ml LPS and after 30min Brefeldin A (GolgiPlug, BD Biosciences) was added. After 8h of LPS stimulation, cells were harvested, fixed and stained for Tnf (Ramirez-Ortiz et al, 2015) and Cd11c, and FACS sorted (Supplemental Experimental Procedures). The genome-wide screens were performed as three independent replicates; in the first screen, 60 million infected cells yielded 350 million cells at day 9, while in the second and third screens, 200 million infected cells yielded 1 billion BMDCs at day 9.…”

Section: Methodsmentioning

confidence: 99%

A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks

Parnas

Jovanović

Eisenhaure

et al. 2015

Cell

Self Cite

410

374

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Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in the known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS, and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells, and provide a genetic approach for dissection of mammalian cell circuits.

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The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity

Cited by 65 publications

References 45 publications

Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells

Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells

CLEC5A-Mediated Enhancement of the Inflammatory Response in Myeloid Cells Contributes to Influenza Virus Pathogenicity In Vivo

A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks

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