Faculty Opinions recommendation of Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.

2019 ◽  
Author(s):  
Guy Zimmerman ◽  
Karin Chen ◽  
Christian Con Yost
Keyword(s):  
B Cells ◽  
Hidradenitis Suppurativa ◽  
Neutrophil Extracellular Traps ◽  
Immune Dysregulation ◽  
Type I Interferons ◽  
Type I ◽  
Extracellular Traps

Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa

2019 ◽  
Vol 11 (508) ◽  
pp. eaav5908 ◽  
Author(s):  
Angel S. Byrd ◽  
Carmelo Carmona-Rivera ◽  
Liam J. O’Neil ◽  
Philip M. Carlucci ◽  
Cecilia Cisar ◽  
...  
Keyword(s):  
Hidradenitis Suppurativa ◽  
Plasma Cells ◽  
Neutrophil Extracellular Traps ◽  
Gene Signature ◽  
Immune Dysregulation ◽  
Type I Interferons ◽  
Unknown Etiology ◽  
Acne Inversa ◽  
Type I ◽  
Extracellular Traps

Hidradenitis suppurativa (HS), also known as acne inversa, is an incapacitating skin disorder of unknown etiology manifested as abscess-like nodules and boils resulting in fistulas and tissue scarring as it progresses. Given that neutrophils are the predominant leukocyte infiltrate in HS lesions, the role of neutrophil extracellular traps (NETs) in the induction of local and systemic immune dysregulation in this disease was examined. Immunofluorescence microscopy was performed in HS lesions and detected the prominent presence of NETs. NET complexes correlated with disease severity, as measured by Hurley staging. Neutrophils from the peripheral blood of patients with HS peripheral also displayed enhanced spontaneous NET formation when compared to healthy control neutrophils. Sera from patients recognized antigens present in NETs and harbored increased antibodies reactive to citrullinated peptides. B cell dysregulation, as evidenced by elevated plasma cells and IgG, was observed in the circulation and skin from patients with HS. Peptidylarginine deiminases (PADs) 1 to 4, enzymes involved in citrullination, were differentially expressed in HS skin, when compared to controls, in association with enhanced tissue citrullination. NETs in HS skin coexisted with plasmacytoid dendritic cells, in association with a type I interferon (IFN) gene signature. Enhanced NET formation and immune responses to neutrophil and NET-related antigens may promote immune dysregulation and contribute to inflammation. This, along with evidence of up-regulation of the type I IFN pathway in HS skin, suggests that the innate immune system may play important pathogenic roles in this disease.

The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps

2021 ◽  
Vol 14 (673) ◽  
pp. eaax7942
Author(s):  
Falko Apel ◽  
Liudmila Andreeva ◽  
Lorenz Sebastian Knackstedt ◽  
Robert Streeck ◽  
Christian Karl Frese ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Neutrophil Extracellular Traps ◽  
Type I Interferons ◽  
Type I ◽  
Immune Cell Activation ◽  
Extracellular Traps ◽  
Regulated Cell Death

Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN production. The NET-associated serine protease neutrophil elastase (NE) mediated the activation of this pathway. We showed that NET induction in mice treated with the lectin concanavalin A, a model of autoimmune hepatitis, resulted in cGAS-dependent stimulation of an IFN response, suggesting that NETs activated cGAS in vivo. Thus, our findings suggest that cGAS is a sensor of NETs, mediating immune cell activation during infection.

scholarly journals 1018 Neutrophil extracellular traps and type 1 IFN contribute to autoimmunity in hidradenitis suppurativa

2018 ◽  
Vol 138 (5) ◽  
pp. S173
Author(s):  
A.S. Byrd ◽  
C. Carmona-Rivera ◽  
P.A. Carlucci ◽  
M.L. Kerns ◽  
J.A. Caffrey ◽  
...  
Keyword(s):  
Hidradenitis Suppurativa ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps

scholarly journals Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure

2017 ◽  
Vol 91 ◽  
pp. 225-237 ◽  
Author(s):  
Anna M. Gram ◽  
Chenglong Sun ◽  
Sanne L. Landman ◽  
Timo Oosenbrug ◽  
Hester J. Koppejan ◽  
...  
Keyword(s):  
B Cells ◽  
Type I Interferons ◽  
Type I ◽  
Human B Cells ◽  
Cytoplasmic Dna

scholarly journals Role of type I interferons in the activation of autoreactive B cells

2012 ◽  
Vol 90 (5) ◽  
pp. 498-504 ◽  
Author(s):  
Kerstin Kiefer ◽  
Michael A Oropallo ◽  
Michael P Cancro ◽  
Ann Marshak‐Rothstein
Keyword(s):  
B Cells ◽  
Type I Interferons ◽  
Type I ◽  
Autoreactive B Cells

scholarly journals Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke

Blood ◽  
2021 ◽  
Author(s):  
Ranran Wang ◽  
Yuanbo Zhu ◽  
Zhongwang Liu ◽  
Luping Chang ◽  
Xiaofei Bai ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Thrombolytic Therapy ◽  
Clinical Problem ◽  
Neutrophil Extracellular Traps ◽  
Artery Occlusion ◽  
Type I ◽  
Brain Hemorrhage ◽  
Extracellular Traps ◽  
Dnase 1

Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains in tPA-treated mice. Blood-brain barrier (BBB) disruption following ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase 1 or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase 1 or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase 1-mediated downregulation of the STING pathway and type I interferon (IFN) production, and blocked the antihemorrhagic effect of DNase 1 in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in ischemic brain, and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.

scholarly journals Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Clara Lawler ◽  
Philip G. Stevenson
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
B Cell ◽  
Natural Infection ◽  
Lytic Infection ◽  
Type I Interferons ◽  
Type I ◽  
Cell Infection ◽  
Host Colonization ◽  
Herpesvirus 4

ABSTRACT Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied in vivo. Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alert mice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c+ cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I-based interventions to reduce host colonization. IMPORTANCE Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon-based therapeutic intervention.

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