scholarly journals Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation

2019 ◽  
Vol 217 (3) ◽  
Author(s):  
Yi-Ling Chen ◽  
Tomas Gomes ◽  
Clare S. Hardman ◽  
Felipe A. Vieira Braga ◽  
Danuta Gutowska-Owsiak ◽  
...  
Keyword(s):  
Human Skin ◽  
Type I Interferon ◽  
Skin Inflammation ◽  
Sterile Inflammation ◽  
Type I ◽  
Skin Wounds ◽  
Healthy Human ◽  
Lymph Node Homing ◽  
Single Cell Rna Sequencing ◽  
Skin Infiltration

Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) and are traditionally defined as being BDCA-2+CD123+. pDCs are not readily detectable in healthy human skin, but have been suggested to accumulate in wounds. Here, we describe a CD1a-bearing BDCA-2+CD123int DC subset that rapidly infiltrates human skin wounds and comprises a major DC population. Using single-cell RNA sequencing, we show that these cells are largely activated DCs acquiring features compatible with lymph node homing and antigen presentation, but unexpectedly express both BDCA-2 and CD123, potentially mimicking pDCs. Furthermore, a third BDCA-2–expressing population, Axl+Siglec-6+ DCs (ASDC), was also found to infiltrate human skin during wounding. These data demonstrate early skin infiltration of a previously unrecognized CD123intBDCA-2+CD1a+ DC subset during acute sterile inflammation, and prompt a re-evaluation of previously ascribed pDC involvement in skin disease.

scholarly journals Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

2019 ◽  
Author(s):  
Helen Heath ◽  
Gary Britton ◽  
Hiromi Kudo ◽  
George Renney ◽  
Malcolm Ward ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Pancreatitis ◽  
Type I Interferon ◽  
Pancreatic Tissue ◽  
Sterile Inflammation ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Label Free ◽  
Bone Marrow Chimera ◽  
Interferon Signalling

ABSTRACTSeverity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However its role in sterile inflammation is unknown. We hypothesised that Stat2 determines severity of non-infective inflammation in the pancreas.Wild type (WT) and Stat2−/− mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2−/− bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells.Stat2−/− mice were protected from cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2−/− mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2−/− mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/Stat2−/− bone-marrow chimera were protected from pancreatitis irrespective of host or recipient genotype.Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow derived cells.

scholarly journals Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

2016 ◽  
Vol 213 (5) ◽  
pp. 697-713 ◽  
Author(s):  
Simone Caielli ◽  
Shruti Athale ◽  
Bojana Domic ◽  
Elise Murat ◽  
Manjari Chandra ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Type I Interferon ◽  
High Mobility ◽  
Human Neutrophils ◽  
Type I ◽  
Healthy Human ◽  
Mitochondrial Nucleoids ◽  
Blood Neutrophils ◽  
Mitochondrial Origin

Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.

Sign in / Sign up

Export Citation Format

Share Document