Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents.
Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
Pubmed ID: 38200007 RIS Download
Research resources used in this publication
None foundAdditional research tools detected in this publication
- Gene Ontology (RRID:SCR_002811)
- HTSeq (RRID:SCR_005514)
- KOBAS (RRID:SCR_006350)
- Promega (RRID:SCR_006724)
- PeproTech (RRID:SCR_006802)
- DEGseq (RRID:SCR_008480)
- FlowJo (RRID:SCR_008520)
- Millipore (RRID:SCR_008983)
- Proteintech Group (RRID:SCR_008986)
- Trimmomatic (RRID:SCR_011848)
- KEGG (RRID:SCR_012773)
- Abcam (RRID:SCR_012931)
- Agilent Technologies (RRID:SCR_013575)
- HISAT2 (RRID:SCR_015530)
- BALB/cAnNCrl (RRID:MGI:2683685)
- C57BL/6J (RRID:IMSR_JAX:000664)
Antibodies used in this publication
- Rabbit Anti-Rat IgG - H&L Polyclonal Antibody, FITC Conjugated (RRID:AB_955327)
- Phospho-RELA-S536 pAb (RRID:AB_2771511)
- Phospho-RELA-S529 Rabbit pAb (RRID:AB_2863855)
- Phospho-RELA-S468 pAb (RRID:AB_2771508)
- Phospho-RELA-S276 pAb (RRID:AB_2771505)
- Rat Notch-1 Affinity Purified Polyclonal Ab (RRID:AB_2153372)
- IRDye 800CW Goat anti-Rabbit IgG (RRID:AB_621843)
- IRDye 680RD Goat anti-Mouse IgG (RRID:AB_2651128)
- Human Anti-Human Rela-p65, aa 456-551 Affinity purified Polyclonal antibody, Unconjugated (RRID:AB_2179033)
- Goat Anti-Rabbit IgG - H&L Polyclonal Antibody, Cy5 ?? Conjugated (RRID:AB_955061)
- Goat Anti-Rabbit IgG - H&L Polyclonal Antibody, Cy3 ?? Conjugated (RRID:AB_955021)
- Goat Anti-Mouse IgG - H&L Polyclonal Antibody, Cy5 ?? Conjugated (RRID:AB_955068)
- Goat anti-Mouse IgG H&L (Cy3 ®) secondary antibody (RRID:AB_10680176)
- Donkey Anti-Goat IgG - H&L Polyclonal antibody, Cy3 ?? Conjugated (RRID:AB_955018)
- Anti-beta Tubulin antibody - Loading Control (RRID:AB_2210370)
- Rabbit monoclonal STAT3 (EPR787Y) antibody (RRID:AB_2889877)
- STAT3 (phospho S727) antibody [E121-31] (RRID:AB_2286742)
- STAT1 antibody (RRID:AB_882708)
- STAT1 (phospho Y701) antibody (RRID:AB_779082)
- Recombinant Anti-STAT1 (phospho S727) antibody [EPR3146] (RRID:AB_10863745)
- NOTCH3 antibody (RRID:AB_776841)
- Rabbit Anti-Notch1 Monoclonal Antibody, Unconjugated, Clone EP1238Y (RRID:AB_881725)
- Rabbit Anti-Human NFkB p65, phospho (Ser536) Polyclonal Antibody, Unconjugated (RRID:AB_1925243)
- NFkB p65 (phospho S529) antibody (RRID:AB_10681170)
- Rabbit Anti-NFkB p65, phospho (Ser468) Polyclonal Antibody, Unconjugated (RRID:AB_881299)
- Mouse Anti-Myc tag Monoclonal Antibody, Unconjugated, Clone 9E10 (RRID:AB_303599)
- Anti-Lamin B1 antibody - Nuclear Envelope Marker (RRID:AB_443298)
- Jagged1 antibody (RRID:AB_2280547)
- Rabbit Anti-IKB alpha Monoclonal Antibody, Unconjugated, Clone E130 (RRID:AB_733068)
- IKB alpha (phospho S32) antibody [EPR3148] (RRID:AB_10562951)
- Phospho IKB alpha (S36) antibody (RRID:AB_2801653)
- Anti-IRF5 antibody [EPR17067] (RRID:AB_2801301)
- IRF-4 (F-4) (RRID:AB_627828)
- Recombinant Anti-iNOS antibody [EPR16635] (RRID:AB_2861417)
- Rabbit Anti-IKK alpha + IKK beta, phospho (Ser180 / Ser181) Polyclonal Antibody, Unconjugated (RRID:AB_883038)
- Rabbit Anti-HA tag Polyclonal Antibody, Unconjugated (RRID:AB_307019)
- GFP-avictoria (RRID:AB_303395)
- GAPDH antibody [6C5] (RRID:AB_2107448)
- F4/80 antibody [CI:A3-1] (RRID:AB_1140040)
- Recombinant Anti-ERK1 + ERK2 antibody [EPR17526] (RRID:AB_2802136)
- Mouse Anti-T7 tag Monoclonal Antibody, Unconjugated, Clone F-tag-01 (RRID:AB_444336)
- Rabbit Anti-CD34 Monoclonal Antibody, Unconjugated, Clone EP373Y (RRID:AB_1640331)
- Rabbit Anti-activated Notch1 Polyclonal Antibody, Unconjugated (RRID:AB_306863)
- Rabbit Anti-NFkB p65 Polyclonal Antibody, Unconjugated (RRID:AB_443394)
- T-bet (RRID:AB_10611726)
- Mouse Anti-Human TNF Monoclonal Antibody, PerCP-Cy5.5 Conjugated, Clone MAB11 (RRID:AB_1727579)
- iNOS Monoclonal Antibody (CXNFT), PE, eBioscience (RRID:AB_2572642)
- IL-12 (p40/p70) (RRID:AB_395420)
- PE Rat Anti-Mouse F4/80 Antibody (RRID:AB_2687527)
- CD86 (RRID:AB_10896971)
- Mouse Anti-IL-8 Monoclonal Antibody, Phycoerythrin Conjugated, Clone G265-8 (RRID:AB_395529)
- PE Mouse anti-Human FoxP3 Clone 236A/E7 (RRID:AB_10563418)
- CD80 (RRID:AB_395039)
- Mouse Anti-Human GATA3 Monoclonal Antibody, PE-Cy???7 Conjugated (RRID:AB_1645544)
- Rat Anti-TNF Monoclonal Antibody, FITC Conjugated, Clone MP6-XT22 (RRID:AB_395379)
- Rat Anti-Ly-6C Monoclonal Antibody, FITC Conjugated, Clone AL-21 (RRID:AB_394628)
- Rat Anti-IL-10 Monoclonal Antibody, FITC Conjugated, Clone JES5-16E3 (RRID:AB_395411)
- BV650 Mouse Anti-Human CD11c (RRID:AB_2732048)
- Ms CD192 (CCR2) BV605 475301 50ug (RRID:AB_2872430)
- CD25 (IL-2 Receptor α) (RRID:AB_2744343)
- CD206 (Mannose Receptor) (RRID:AB_2740147)
- IFN-γ (RRID:AB_2738118)
- CD14 (RRID:AB_2737993)
- F4/80 (RRID:AB_2739313)
- IL-10 (RRID:AB_2738566)
- RORγt (RRID:AB_2738114)
- Ms TNF BB700 MP6-XT22 (RRID:AB_2869775)
- CD197 (CCR7) (RRID:AB_2744307)
- Ms CD11C BB700 HL3 (RRID:AB_2869773)
- CD4 (RRID:AB_2744419)
- IL-17A (RRID:AB_2739087)
- Rat Anti-CD11b Monoclonal Antibody, APC-Cy7 Conjugated, Clone M1/70 (RRID:AB_396772)
- Mouse Anti-CD3 Monoclonal Antibody, APC-Cy7 Conjugated, Clone SK7 (RRID:AB_396890)
- Mouse Anti-CD16 Monoclonal Antibody, APC-Cy7 Conjugated, Clone 3G8 (RRID:AB_396864)
- CD206 (Mannose Receptor) (RRID:AB_2739133)
- CD14 (RRID:AB_2739340)
- IL-6 (RRID:AB_10694253)
Associated grants
- Agency: National Natural Science Foundation of China (National Science Foundation of China),
Id: 31970148 - Agency: National Natural Science Foundation of China (National Science Foundation of China),
Id: 82202367
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
Gene Ontology (tool)
RRID:SCR_002811
Computable knowledge regarding functions of genes and gene products. GO resources include biomedical ontologies that cover molecular domains of all life forms as well as extensive compilations of gene product annotations to these ontologies that provide largely species-neutral, comprehensive statements about what gene products do. Used to standardize representation of gene and gene product attributes across species and databases.
View all literature mentionsHTSeq (tool)
RRID:SCR_005514
THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.
View all literature mentionsKOBAS (tool)
RRID:SCR_006350
Web server to identify statistically enriched pathways, diseases, and GO terms for a set of genes or proteins, using pathway, disease, and GO knowledge from multiple famous databases. It allows for both ID mapping and cross-species sequence similarity mapping. It then performs statistical tests to identify statistically significantly enriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). A standalone command line version is also available
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RRID:SCR_008480
R package to identify differentially expressed genes from RNA-Seq data.
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Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
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RRID:SCR_008986
Proteintech Europe Ltd is an ISO 9001:2008 certified company
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RRID:SCR_011848
Software Java pipeline for trimming tasks for Illumina paired end and single ended data. Flexible Trimmer for Illumina Sequence Data. Pair aware preprocessing tool optimized for Illumina next generation sequencing data. Includes several processing steps for read trimming and filtering. Operating systems Unix/Linux, Mac OS, Windows.
View all literature mentionsKEGG (tool)
RRID:SCR_012773
Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.
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RRID:SCR_012931
A commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
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RRID:SCR_013575
Company provides laboratories worldwide with analytical instruments and supplies, clinical and diagnostic testing services, consumables, applications and expertise in life sciences and applied chemical markets.
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Graph-based alignment of next generation sequencing reads to a population of genomes.
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RRID:MGI:2683685
laboratory mouse with name BALB/cAnNCrl from MGI.
View all literature mentionsC57BL/6J (tool)
RRID:IMSR_JAX:000664
Mus musculus with name C57BL/6J from IMSR.
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RRID:AB_2153372
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RRID:AB_621843
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RRID:AB_2651128
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RRID:AB_2179033
This polyclonal targets Human RelA-p65, aa 456-551
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RRID:AB_955061
This polyclonal targets Rabbit Rabbit IgG secondary - H&L
View all literature mentionsGoat Anti-Rabbit IgG - H&L Polyclonal Antibody, Cy3 ?? Conjugated (antibody)
RRID:AB_955021
This polyclonal targets Rabbit Rabbit IgG secondary - H&L
View all literature mentionsGoat Anti-Mouse IgG - H&L Polyclonal Antibody, Cy5 ?? Conjugated (antibody)
RRID:AB_955068
This polyclonal targets Mouse Mouse IgG secondary - H&L
View all literature mentionsGoat anti-Mouse IgG H&L (Cy3 ®) secondary antibody (antibody)
RRID:AB_10680176
This polyclonal targets Goat anti-Mouse IgG H&L (Cy3 ®) secondary antibody
View all literature mentionsDonkey Anti-Goat IgG - H&L Polyclonal antibody, Cy3 ?? Conjugated (antibody)
RRID:AB_955018
This polyclonal targets Goat Goat IgG secondary - H&L
View all literature mentionsAnti-beta Tubulin antibody - Loading Control (antibody)
RRID:AB_2210370
This polyclonal targets beta Tubulin
View all literature mentionsRabbit monoclonal STAT3 (EPR787Y) antibody (antibody)
RRID:AB_2889877
This recombinant monoclonal targets STAT3
View all literature mentionsSTAT3 (phospho S727) antibody [E121-31] (antibody)
RRID:AB_2286742
This monoclonal targets STAT3
View all literature mentionsSTAT1 antibody (antibody)
RRID:AB_882708
This polyclonal targets STAT1 antibody
View all literature mentionsSTAT1 (phospho Y701) antibody (antibody)
RRID:AB_779082
This polyclonal targets STAT1 (phospho Y701)
View all literature mentionsRecombinant Anti-STAT1 (phospho S727) antibody [EPR3146] (antibody)
RRID:AB_10863745
This recombinant monoclonal targets STAT1 (phospho S727)
View all literature mentionsNOTCH3 antibody (antibody)
RRID:AB_776841
This polyclonal targets NOTCH3 antibody
View all literature mentionsRabbit Anti-Notch1 Monoclonal Antibody, Unconjugated, Clone EP1238Y (antibody)
RRID:AB_881725
This monoclonal targets Notch1
View all literature mentionsRabbit Anti-Human NFkB p65, phospho (Ser536) Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_1925243
This polyclonal targets Human NFkB p65, phospho (Ser536)
View all literature mentionsNFkB p65 (phospho S529) antibody (antibody)
RRID:AB_10681170
This polyclonal targets NFkB p65 (phospho S529) antibody
View all literature mentionsRabbit Anti-NFkB p65, phospho (Ser468) Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_881299
This polyclonal targets NFkB p65 (phospho S468)
View all literature mentionsMouse Anti-Myc tag Monoclonal Antibody, Unconjugated, Clone 9E10 (antibody)
RRID:AB_303599
This monoclonal targets c-Myc
View all literature mentionsAnti-Lamin B1 antibody - Nuclear Envelope Marker (antibody)
RRID:AB_443298
This polyclonal targets LMNB1
View all literature mentionsJagged1 antibody (antibody)
RRID:AB_2280547
This polyclonal targets Jag1
View all literature mentionsRabbit Anti-IKB alpha Monoclonal Antibody, Unconjugated, Clone E130 (antibody)
RRID:AB_733068
This monoclonal targets IKB alpha
View all literature mentionsIKB alpha (phospho S32) antibody [EPR3148] (antibody)
RRID:AB_10562951
This monoclonal targets IKB alpha (phospho S32) antibody [EPR3148]
View all literature mentionsPhospho IKB alpha (S36) antibody (antibody)
RRID:AB_2801653
This monoclonal targets IKB alpha
View all literature mentionsAnti-IRF5 antibody [EPR17067] (antibody)
RRID:AB_2801301
This monoclonal targets IRF5
View all literature mentionsRecombinant Anti-iNOS antibody [EPR16635] (antibody)
RRID:AB_2861417
This recombinant targets iNOS
View all literature mentionsRabbit Anti-IKK alpha + IKK beta, phospho (Ser180 / Ser181) Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_883038
This polyclonal targets IKK alpha + IKK beta (phospho S180 + S181)
View all literature mentionsRabbit Anti-HA tag Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_307019
This polyclonal targets HA tag - ChIP Grade
View all literature mentionsGAPDH antibody [6C5] (antibody)
RRID:AB_2107448
This monoclonal targets GAPDH antibody [6C5]
View all literature mentionsF4/80 antibody [CI:A3-1] (antibody)
RRID:AB_1140040
This monoclonal targets F4/80 antibody [CI:A3-1]
View all literature mentionsRecombinant Anti-ERK1 + ERK2 antibody [EPR17526] (antibody)
RRID:AB_2802136
This recombinant targets ERK1 + ERK2
View all literature mentionsMouse Anti-T7 tag Monoclonal Antibody, Unconjugated, Clone F-tag-01 (antibody)
RRID:AB_444336
This monoclonal targets DDDDK tag
View all literature mentionsRabbit Anti-CD34 Monoclonal Antibody, Unconjugated, Clone EP373Y (antibody)
RRID:AB_1640331
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RRID:AB_306863
This polyclonal targets activated Notch1
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RRID:AB_443394
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RRID:AB_1727579
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RRID:AB_2572642
This monoclonal targets iNOS
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RRID:AB_395420
This monoclonal targets IL-12
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RRID:AB_2687527
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RRID:AB_395529
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RRID:AB_10563418
This monoclonal targets FoxP3
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RRID:AB_1645544
This monoclonal targets Human GATA3
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RRID:AB_394628
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RRID:AB_395411
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RRID:AB_2732048
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View all literature mentionsMs CD192 (CCR2) BV605 475301 50ug (antibody)
RRID:AB_2872430
This monoclonal targets CD192 (CCR2)
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RRID:AB_2744343
This monoclonal targets CD25 (IL-2 Receptor α)
View all literature mentionsCD206 (Mannose Receptor) (antibody)
RRID:AB_2740147
This monoclonal targets CD206 (Mannose Receptor)
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RRID:AB_2869775
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View all literature mentionsCD197 (CCR7) (antibody)
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This monoclonal targets CD197 (CCR7)
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RRID:AB_2869773
This monoclonal targets CD11c
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RRID:AB_396772
This monoclonal targets CD11b
View all literature mentionsMouse Anti-CD3 Monoclonal Antibody, APC-Cy7 Conjugated, Clone SK7 (antibody)
RRID:AB_396890
This monoclonal targets CD3
View all literature mentionsMouse Anti-CD16 Monoclonal Antibody, APC-Cy7 Conjugated, Clone 3G8 (antibody)
RRID:AB_396864
This monoclonal targets CD16 (FcγRIII)
View all literature mentionsCD206 (Mannose Receptor) (antibody)
RRID:AB_2739133
This monoclonal targets CD206 (Mannose Receptor)
View all literature mentions
