Altered compensatory cytokine signaling underlies the discrepancy between <i>Flt3–/–</i> and <i>Flt3l–/–</i> mice

Durai, Vivek; Bagadia, Prachi; Briseño, Carlos G.; Theisen, Derek J.; Iwata, Arifumi; Davidson, Jesse T.; Gargaro, Marco; Fremont, Daved H.; Murphy, Theresa L.; Murphy, Kenneth M.

doi:10.1084/jem.20171784

Cited by 47 publications

(51 citation statements)

References 61 publications

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“…Lymphoid and nonlymphoid organ DCs were harvested and prepared as described previously 48 . Briefly, spleens and inguinal skin-draining LNs were minced and digested in 5 mL of Iscove’s modified Dulbecco’s media (IMDM) + 10% FCS (cIMDM) with 250 µg/mL collagenase B (Roche) and 30 U/mL DNaseI (Sigma-Aldrich) for 45 min at 37⁰C with stirring.…”

Section: Methodsmentioning

confidence: 99%

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

et al. 2019

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Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. Here we identified Irf8 enhancers via chromatin profiling of DCs and used CRISPR/Cas9 genome editing to assess their roles in Irf8 regulation. An enhancer 32 kilobases downstream of the Irf8 transcriptional start site (+32 kb Irf8 ) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41 kb Irf8 enhancer previously thought to be active only in plasmacytoid DCs was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41 kb Irf8 enhancer in DC progenitors is responsible for cDC1 fate specification.

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Section: Methodsmentioning

confidence: 99%

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

et al. 2019

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“…Heatmap comparing the expression of all chemokines and their receptors expressed in murine BM DCs and spleen (Sp) cDC2s (Gene Expression Omnibus database, accession no. GSE110789) (49). Data are mean ± SEM.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking

Zhang¹,

Supakorndej²,

Krambs³

et al. 2019

Journal of Clinical Investigation

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“…Dendritic cells were isolated from bone marrows of C57BL/6 mice by crushing tibias, femurs, and hips in MACS buffer as previously described (15). Extracted cells were filtered through a 40 µm cell strainer and centrifuged at 300 × g for 5 min.…”

Section: Preparationmentioning

confidence: 99%

Pharmacologic Induction of Endotoxin Tolerance in Dendritic Cells by L-Kynurenine

et al. 2020

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Endotoxin tolerance aims at opposing hyperinflammatory responses to lipopolysaccharide (LPS) exposure. The aryl hydrocarbon receptor (AhR) participates in protection against LPS-mediated tissue damage, as it plays a necessary role in restraining the proinflammatory action of IL-1β and TNF-α while fostering the expression of protective TGF-β. TGF-β, in turn, promotes durable expression of the immune regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 degrades L-tryptophan to L-kynurenine-an activating ligand for AhR-thus establishing a feed-forward loop. In this study, we further demonstrate that L-kynurenine also promotes the dissociation of the Src kinase-AhR cytosolic complex, leading to the activation of both genomic and non-genomic events in conventional dendritic cells (cDCs) primed with LPS. Specifically, the Src kinase, by phosphorylating the downstream target IDO1, triggers IDO1's signaling ability, which results in enhanced production of TGF-β, an event key to establishing full endotoxin tolerance. We demonstrated that exogenous L-kynurenine can substitute for the effects of continued or repeated LPS exposure and that the AhR-Src-IDO1 axis represents a critical step for the transition from endotoxin susceptibility to tolerance. Moreover, much like fully endotoxin-tolerant dendritic cells (DCs) (i.e., treated twice with LPS in vitro), DCs-treated once with LPS in vitro and then with kynurenine-confer resistance on naïve recipients to an otherwise lethal LPS challenge. This may have clinical implications under conditions in which pharmacologically induced onset of endotoxin tolerance is a therapeutically desirable event.

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Altered compensatory cytokine signaling underlies the discrepancy between Flt3–/– and Flt3l–/– mice

Abstract: Durai et al. demonstrate that the less severe DC deficiency in Flt3–/– mice compared to Flt3l–/– mice is due to the enhanced sensitivity of Flt3–/– progenitors to compensatory cytokines that support DC development.

Cited by 47 publications

References 61 publications

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification

Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking

Pharmacologic Induction of Endotoxin Tolerance in Dendritic Cells by L-Kynurenine

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