Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo

Bosco, Maria Carla; Pierobon, Daniele; Blengio, Fabiola; Raggi, Federica; Vanni, Cristina; Gattorno, Marco; Eva, Alessandra; Novelli, Francesco; Cappello, Paola; Giovarelli, Mirella; Varesio, Luigi

doi:10.1182/blood-2010-06-292136

Cited by 108 publications

(119 citation statements)

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“…TREM-1 expression is up-regulated by lipopolysaccharide and other microbial products and it functions as an amplifier of the inflammatory response in the context of microbial infections. 11 Bosco et al 1 show that HIF-1 is, at least in part, implicated in the hypoxic-mediated transcriptional activation of TREM-1, consistent with the presence of a putative hypoxia response element in the promoter region. Notably, cross-linking of TREM-1 was associated with induction of DAP12-mediated signaling pathways leading to activation of AKT, ERK-1, and IB␣ and increased production of pro-inflammatory cytokines, indicating that TREM-1 may be involved in amplifying hypoxic-dependent inflammatory responses.…”

mentioning

confidence: 92%

“…Bosco et al report the gene expression profiling of hypoxic mature DCs and identify TREM-1 as a novel hypoxia-inducible gene that may amplify inflammatory responses. 1 N ormal oxygen delivery is essential for survival of metazoan organisms and evolutionarily conserved mechanisms have been developed to maintain oxygen homeostasis. Changes in tissue oxygen levels in pathologic conditions are caused by an imbalance between cellular oxygen demand and tissue oxygen delivery.…”

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confidence: 99%

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Hypoxia: jump-starting inflammation

Melillo

2011

Blood

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confidence: 92%

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confidence: 99%

Hypoxia: jump-starting inflammation

Melillo

2011

Blood

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“…Macrophages were recovered using 5 mM EDTA (Life Technologies), reseeded, and cultured overnight with either plate-bound (pb) PGLYRP1 or 3 mg/ml PGN-BS plus 1 mg/ml PGLYRP1, and the supernatants were analyzed for TNF-a using BioPlex (Bio-Rad) or ELISA (R&D Systems). All monocyte/macrophage incubations were done under hypoxic conditions (2% O 2 ) to enhance TREM-1 expression, as previously described for monocyte differentiation to dendritic cells (6). TREM-1 upregulation was confirmed by flow cytometric analysis.…”

Section: Cellular Assaysmentioning

confidence: 99%

Cutting Edge: Identification of Neutrophil PGLYRP1 as a Ligand for TREM-1

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Hjorth

et al. 2015

The Journal of Immunology

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Triggering receptor expressed on myeloid cells (TREM)-1 is an orphan receptor implicated in innate immune activation. Inhibition of TREM-1 reduces sepsis in mouse models, suggesting a role for it in immune responses triggered by bacteria. However, the absence of an identified ligand has hampered a full understanding of TREM-1 function. We identified complexes between peptidoglycan recognition protein 1 (PGLYRP1) and bacterially derived peptidoglycan that constitute a potent ligand capable of binding TREM-1 and inducing known TREM-1 functions. Interestingly, multimerization of PGLYRP1 bypassed the need for peptidoglycan in TREM-1 activation, demonstrating that the PGLYRP1/TREM-1 axis can be activated in the absence of bacterial products. The role for PGLYRP1 as a TREM-1 activator provides a new mechanism by which bacteria can trigger myeloid cells, linking two known, but previously unrelated, pathways in innate immunity.

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“…SEMA4D has been reported to inhibit immune-cell migration (12), and its expression may be regulated by hypoxia (13)(14)(15) and other cues within the TME. TAMs have been reported to be a necessary source of SEMA4D within the TME (16).…”

Section: Introductionmentioning

confidence: 99%

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

Evans

Jonason

Bussler

et al. 2015

Cancer Immunology Research

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Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2 þ mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression. Cancer Immunol Res; 3(6); 689-701. Ó2015 AACR.

show abstract

Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo

Cited by 108 publications

References 51 publications

Hypoxia: jump-starting inflammation

Hypoxia: jump-starting inflammation

Cutting Edge: Identification of Neutrophil PGLYRP1 as a Ligand for TREM-1

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

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