Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7

Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNβ and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.

Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

Autophagy: A Friend or Foe in Allergic Asthma?

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.

Serum Molecular Biomarkers in Neuromyelitis Optical and Multiple Sclerosis

ObjectiveThe aims of this study were to determine whether the expression levels of serological cytokines could distinguish 1) neuromyelitis optical spectrum disorders (NMOSD) from healthy controls (HCs); and 2) NMOSD patients with and without the aquaporin-4 (AQP-4) antibody biomarker from each other; and 3) NMOSD patients without antibody to AQP-4 from multiple sclerosis (MS). MethodsThe expression levels of 200 proteins in serum from 41 NMOSD (32 with antibodies to AQP-4, 9 without antibodies to AQP-4), 12 MS patients, and 34 HCs were measured using glass-based antibody arrays. In parallel, the correlation between protein expression in NMOSD/MS patients and clinical traits was analyzed with Weighted Gene Co-expression Network Analysis (WGCNA).ResultsThirty-nine serological proteins were differentially expressed in NMOSD patients compared to HCs. 29 differentially-expression proteins (DEPs) were specific to NMOSD whereas 10 of these were observed in NMOSD and MS samples. In addition, there were 15 DEPs between AQP-4-IgG seronegative and AQP-4-IgG seropositive NMOSD patients, and 9 DEPs between NMOSD and MS patients who did not have AQP-4-IgG. ConclusionsOur findings highlight that serological Interleukin-17B (IL-17B) may be key biomarker of NMOSD and MS. While epidermal growth factor (EGF) may be correlated with the breakdown of the blood-brain barrier in NMOSD patients, granulocyte chemotactic protein-2 (GCP-2) and monocyte differentiation antigen CD14 (CD14) may play different roles in the pathogenesis of AQP-4-IgG seronegative and seropositive NMOSD and MS. Novel biomarkers identified in our study could potentially be used in the diagnosis and treatment of NMOSD.Trial registrationPublic title: Multi-Center Clinical Study of GFAP AstrocytopathyRegistration number: ChiCTR2000041291Date of registration: 2020-12-23 (Retrospective registration)URL of trail registry record: http://www.chictr.org.cn/showproj.aspx?proj=65306