Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

Pène, Frédéric; Courtine, Emilie; Ouaaz, Fatah; Zuber, Benjamin; Sauneuf, Bertrand; Sirgo, G.; Rousseau, C.; Toubiana, Julie; Balloy, Viviane; Chignard, Michel; Mira, Jean‐Paul; Chiche, Jean‐Daniel

doi:10.1128/iai.00238-09

Cited by 49 publications

(36 citation statements)

References 31 publications

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“…Because of its potent Ag presentation properties, DCs are required for induction of immune responses at the onset of infection and quantitative, and functional loss of DCs has been attributed to severity of infectious diseases. 56,57 In this context, our studies raise the possibility that nonsteroidal anti-inflammatory agents inhibiting PGE 2 biosynthesis, particularly when taken over extended periods of time, may exacerbate disease as a consequence of reduced DC generation. In addition, several experimental and clinical studies support the use of DC vaccines 58 ; however, current DC vaccines are not optimal for the treatment of human diseases.…”

Section: Discussionmentioning

confidence: 99%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E 2 (PGE 2 ) is required for optimal IntroductionDendritic cells (DCs) are specialized Ag-presenting immune cells that induce adaptive immune responses and maintain self-tolerance and are attractive targets for therapeutic manipulation of the immune system. 1,2 Two main DC subsets have been identified on the basis of their location, phenotype, and function: Ag-presenting classic DC (cDC) and type I IFN-producing plasmacytoid DC (pDC), 3,4 and are generated from Flt3-expressing hematopoietic progenitor cells in the BM. 5,6 Recent studies identified a common DC, monocyte and macrophage precursor designated as macrophage DC progenitor cell (MDP) 7,8 and a common DC progenitor (CDP) that is restricted to DC development. 9 MDPs differentiate to CDPs, which in turn give rise to cDCs and pDCs, but not monocytes, and finally to pre-cDCs, 10 a committed precursor of cDCs. 11,12 Unlike MDPs and CDPs that differentiate within the BM, pre-cDCs traffic to secondary lymphoid organs where they further differentiate into cDCs. 4,13 In addition, monocytes can also develop a DC phenotype under inflammatory conditions. 14,15 Flt3 (also known as Flk2 and CD135) is a receptor tyrosine kinase that is broadly expressed on early BM hematopoietic progenitor cells (HPCs), including DC progenitor cells. 5,9,16 Mice with a deficiency in Flt3 or Flt3 ligand (Flt3L) have reduced DC numbers, 13,17 whereas administration of Flt3L dramatically increases BM and peripheral DCs. 18 Although Flt3 signaling is crucial for DC generation from their progenitor cells at steady state, the normal physiologic mechanisms that control Flt3 expression and regulate Flt3L-dependent DC differentiation remain poorly understood.Prostaglandin E 2 (PGE 2 ) is the predominant metabolite of arachidonic acid metabolism produced through the sequential action of phospholipase A 2 , cyclooxygenases (COXs), and PGE synthase. 19,20 There are 2 functionally distinct COX enzyme isoforms, COX1 and COX2, that are encoded by different genes. 20 PGE 2 has been shown to modulate HPC differentiation, inhibiting CFU-GM 21-23 but promoting erythroid burst-forming unit and granulocyte, erythroid, megakaryocyte, and macrophage CFU. 24,25 The long-acting PGE 2 analog, 16,16-dimethyl-PGE 2 (dmPGE 2 ) was shown to increase HSC frequency and engraftment 26,27 and to enhance HSC survival, proliferation, and homing to the BM. 27 Thus, PGE 2 regulates self-renewal and differentiation of HSCs and HPCs, and its effects can differ, depending on hematopoietic cell type and stage of differentiation.The role of PGE 2 in DC maturation and migration under inflammatory conditions is well known. PGE 2 promotes the migration of monocyte-derived and Langerhans DCs, increases their expression of costimulatory molecules, and enhances their ability to stimulate T...

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Section: Discussionmentioning

confidence: 99%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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“…Moreover, the sublethal sepsis enhanced the risk for secondary infections (Fig. 1F) that could be restored through application of naive DC (25). The mechanisms underlying the sustained reduction of the number of splenic DC in post-septic mice have not been investigated so far.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

Pastille

Didovic

Brauckmann

et al. 2011

The Journal of Immunology

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Murine polymicrobial sepsis is associated with a sustained reduction of dendritic cell (DC) numbers in lymphoid organs and with a dysfunction of DC that is considered to mediate the chronic susceptibility of post-septic mice to secondary infections. We investigated whether polymicrobial sepsis triggered an altered de novo formation and/or differentiation of DC in the bone marrow. BrdU labeling experiments indicated that polymicrobial sepsis did not affect the formation of splenic DC. DC that differentiated from bone marrow (bone marrow-derived DC [BMDC]) of post-septic mice released enhanced levels of IL-10 but did not show an altered phenotype in comparison with BMDC from sham mice. Adoptive transfer experiments of BMDC into naive mice revealed that BMDC from post-septic mice impaired Th1 priming but not Th cell expansion and suppressed the innate immune defense mechanisms against Pseudomonas bacteria in the lung. Accordingly, BMDC from post-septic mice inhibited the release of IFN-γ from NK cells that are critical for the protection against Pseudomonas. Additionally, sepsis was associated with a loss of resident DC in the bone marrow. Depletion of resident DC from bone marrow of sham mice led to the differentiation of BMDC that were impaired in Th1 priming similar to BMDC from post-septic mice. Thus, in response to polymicrobial sepsis, DC precursor cells in the bone marrow developed into regulatory DC that impaired Th1 priming and NK cell activity and mediated immunosuppression. The absence of resident DC in the bone marrow after sepsis might have contributed to the modulation of DC differentiation.

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“…Potential prognostic value of the selective depletion of spleen DCs, which are essential to develop an efficient immune response (37), has been reported for patients with sepsis (20) and in animal models of sepsis (32). We have recently shown that TLR2 and TLR4 signaling is involved in the mechanisms leading to depletion of spleen DCs following polymicrobial sepsis (31). Analysis of the expression of proteins involved in TLR signaling in our microarray analysis reveals that only the factor Tollip is downregulated in rel Ϫ/Ϫ mice after CLP (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…DCs link innate immunity and adaptive immunity and are critical in mounting and coordinating host immune responses against infection. Moreover, the importance of DCs in both the early and late phases of sepsis has been established (4,31), with these cells having been reported to be required for survival of polymicrobial sepsis (37). In wt mice, a selective depletion of the spleen lymphoid DC subset CD11c ϩ CD8␣ ϩ was found at day 1, followed by a full replenishment at day 7 after CLP.…”

Section: Sublethal Polymicrobial Sepsis Induces Increased Mortality Imentioning

confidence: 99%

Critical Role of cRel Subunit of NF-κB in Sepsis Survival

et al. 2011

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NF-B is a critical regulator of gene expression during severe infections. NF-B comprises homo-and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLPinduced modifications in gene expression profiles both in wild-type (wt) and in rel ؊/؊ mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel ؊/؊ mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-B member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.

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Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

Cited by 49 publications

References 31 publications

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

Critical Role of cRel Subunit of NF-κB in Sepsis Survival

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