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We previously observed increased levels of adenosine‐deaminase‐acting‐on‐dsRNA (Adar)‐dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR‐dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR‐mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1‐associated protein 1 wild‐type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type‐1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

We previously observed increased levels of adenosine‐deaminase‐acting‐on‐dsRNA (Adar)‐dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR‐dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR‐mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1‐associated protein 1 wild‐type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type‐1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures. [ABSTRACT FROM AUTHOR]

Type 1 interferons play a key role in the pathogenesis of systemic lupus erythematosus (SLE). An important clinical question is whether inhibiting the type 1 interferon pathway reduce the disease activity in SLE patients. This review evaluates the safety and efficacy of the monoclonal antibody against the type 1 interferon alpha receptor, anifrolumab, in patients with SLE. Key terms (SLE, type 1 interferon, anifrolumab) were used to query the PubMed database for phase 1, 2 and 3 clinical trials of anifrolumab for SLE patients. Phase 1 studies showed anifrolumab has non-linear pharmacokinetics and the optimal safe dose is 300 mg given intravenously every four weeks. The MUSE (phase 2) and the TULIP-2 (phase 3) trials showed that anifrolumab when added to standard therapy significantly reduced disease activity in SLE patients. Common adverse events associated with anifrolumab were upper respiratory and urinary infections as well as shingles. Anifrolumab is an exciting new therapeutic for SLE patients. Additional analyses of the combined TULIP-1 and TULIP-2 datasets as well as future studies with anifrolumab will generate yet more data in SLE. No doubt anifrolumab will be studied in other diseases where type I interferons play an important role. [ABSTRACT FROM AUTHOR]

The concept that a breast cancer patient's menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight in this observation. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient's risk for distant metastases.

Objective: This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats., Methods: The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA., Results: APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05)., Conclusion: EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP. Please cite this article as: Ding YY, Xu F, Wang YF, Han LL, Huang SQ, Zhao S, Ma LL, Zhang TH, Zhao WJ, Chen XD. Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway. J Integr Med. 2023; 21(5): 496-508., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

To evaluate the specific response of SLE patients to BNT162b2 vaccination and its impact on autoimmunity defined as in vivo production of interferon-alpha (IFNα) by plasmacytoid dendritic cells (pDCs) and autoreactive immune responses. Our prospective study included SLE patients and healthy volunteers (HV) who received 2 doses of BNT162b2 vaccine 4 weeks apart. Subjects under immunosuppressive drugs or with evidence of prior COVID-19 were excluded. IgG anti-Spike SARS-CoV-2 (anti-S) antibodies, anti-S specific-B cells, anti-S specific T cells, in vivo INF-α production by pDCs, activation marker expression by pDCs and autoreactive anti-nuclear T cells were quantified before first injection, before second injection, and 3 and 6 months after first injection. Vaccinated SLE patients produced significantly lower IgG antibodies and specific B cells against SARS–CoV-2 as compared to HV. In contrast, anti-S T cell response did not significantly differ between SLE patients and HV. Following vaccination, the surface expression of HLA-DR and CD86 and the in vivo production of IFNα by pDCs significantly increased in SLE patients. The boosted expression of HLA-DR on pDCs induced by BNT162b2 vaccine correlated with the overall immune responses against SARS-CoV-2 (anti-S antibodies: r = 0.27 [0.05–0.46], p = 0.02; anti-S B cells: r = 0.19 [-0.03-0.39], p = 0.09); anti-S T cells: r = 0.28 [0.05–0.47], p = 0.016). Eventually, anti-SARS-CoV-2 vaccination was associated with an overall decrease of autoreactive T cells (slope = - 0.00067, p = 0.015). BNT162b2 vaccine induces a transient in vivo activation of pDCs in SLE that contributes to the immune responses against SARS-CoV-2. Unexpectedly BNT162b2 vaccine also dampens the pool of circulating autoreactive T cells, suggesting that vaccination may have a beneficial impact on SLE disease. • a B cell defect impairs immune protection following anti-SARS-Cov-2 vaccine in SLE. • BNT162b2 mRNA induces an in vivo activation of pDCs that contributes to the immune response against SARS-Cov-2 vaccine. • BNT162b2 dampens the pool of circulating autoreactive T cells in SLE suggesting that it may have a beneficial impact on SLE. [ABSTRACT FROM AUTHOR]

Background: Neuro-inflammation has long been implicated as a contributor to the progression of Alzheimer's disease in both humans and animal models. Type-1 interferons (IFNs) are pleiotropic cytokines critical in mediating the innate immune pro-inflammatory response. The production of type-1 IFNs following pathogen detection is, in part, through the activation of the toll-like receptors (TLRs) and subsequent signalling through myeloid differentiation factor-88 (Myd88) and interferon regulatory factors (IRFs). We have previously identified that neuronal type-1 IFN signalling, through the type-1 interferon alpha receptor-1 (IFNAR1), is detrimental in models of AD. Using an in vitro approach, this study investigated the TLR network as a potential production pathway for neuronal type-1 IFNs in response to Aβ. Methods: Wildtype and Myd88-/- primary cultured cortical and hippocampal neurons were treated with 2.5 μM Aβ1-42 for 24 to 72 h or 1 to 10 μM Aβ1-42 for 72 h. Human BE(2)M17 neuroblastoma cells stably expressing an IRF7 small hairpin RNA (shRNA) or negative control shRNA construct were subjected to 7.5 μM Aβ1-42/Aβ42-1 for 24 to 96 h, 2.5 to 15 μM Aβ1-42 for 96 h or 100 ng/ml LPS for 0.5 to 24 h. Q-PCR was used to analyse IFNα, IFNβ, IL-1β, IL-6 and TNFα mRNA transcript levels. Phosphorylation of STAT-3 was detected by Western blot analysis, and cell viability was assessed by MTS assay. Results: Reduced IFNα, IFNβ, IL-1β, IL-6 and TNFα expression was detected in Aβ1-42-treated Myd88-/- neurons compared to wildtype cells. This correlated with reduced phosphorylation of STAT-3, a downstream type-1 IFN signalling mediator. Significantly, Myd88-/- neuronal cultures were protected against Aβ1-42-induced neurotoxicity compared to wildtype as determined by MTS assay. Knockdown of IRF7 in M17 cells was sufficient in blocking IFNα, IFNβ and p-STAT-3 induction to both Aβ1-42 and the TLR4 agonist LPS. M17 IRF7 KD cells were also protected against Aβ1-42-induced cytotoxicity. Conclusions: This study confirms that the neuronal type-1 IFN response to soluble amyloid is mediated primarily through TLRs. This production is dependent upon Myd88 and IRF7 signalling. This study suggests that targeting this pathway to modulate neuronal type-1 IFN levels may be beneficial in controlling Aβ-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Background Hypoxic-ischaemic injuries such as stroke and traumatic brain injury exhibit features of a distinct neuro-inflammatory response in the hours and days post-injury. Microglial activation, elevated pro-inflammatory cytokines and macrophage infiltration contribute to core tissue damage and contribute to secondary injury within a region termed the penumbra. Type-1 interferons (IFNs) are a super-family of pleiotropic cytokines that regulate pro-inflammatory gene transcription via the classical Jak/Stat pathway; however their role in hypoxia-ischaemia and central nervous system neuro-inflammation remains unknown. Using an in vitro approach, this study investigated the role of type-1 IFN signalling in an inflammatory setting induced by oxygen glucose deprivation (OGD). Methods Human BE(2)M17 neuroblastoma cells or cells expressing a type-1 interferon-α receptor 1 (IFNAR1) shRNA or negative control shRNA knockdown construct were subjected to 4.5 h OGD and a time-course reperfusion period (0 to 24 h). Q-PCR was used to evaluate IFNα, IFNβ, IL-1β, IL-6 and TNF-α cytokine expression levels. Phosphorylation of signal transducers and activators of transcription (STAT)-1, STAT-3 and cleavage of caspase-3 was detected by western blot analysis. Post-OGD cellular viability was measured using a MTT assay. Results Elevated IFNα and IFNβ expression was detected during reperfusion post-OGD in parental M17 cells. This correlated with enhanced phosphorylation of STAT-1, a downstream type-1 IFN signalling mediator. Significantly, ablation of type-1 IFN signalling, through IFNAR1 knockdown, reduced IFNα, IFNβ, IL-6 and TNF-α expression in response to OGD. In addition, MTT assay confirmed the IFNAR1 knockdown cells were protected against OGD compared to negative control cells with reduced pro-apoptotic cleaved caspase-3 levels. Conclusions This study confirms a role for type-1 IFN signalling in the neuro-inflammatory response following OGD in vitro and suggests its modulation through therapeutic blockade of IFNAR1 may be beneficial in reducing hypoxia-induced neuro-inflammation. [ABSTRACT FROM AUTHOR]

Okada C, Fazle Akbar SkMd, Horiike N, Onji, M. Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I:C administration.Liver International 2005: 25: 595–603.© Blackwell Munksgaard 2005Primary biliary cirrhosis (PBC) is one of the organ-specific autoimmune diseases characterized by destruction of the biliary epithelial cells, cholestasis, liver cirrhosis, and liver failure. With the postulation that induction of the autoimmune process might induce PBC-like cholangitis, here we used polyinosinic polycytidylic acid (poly I:C), an inducer of type-1 interferon (IFN), to generate an autoimmune cholangitis animal model.Female C57BL/6 mice were injected with 5 mg/kg of poly I:C twice a week for 28 consecutive weeks. Liver specimens were collected to evaluate the degree of cell infiltration. Autoantibodies, including antimitochondrial antibody (AMA), were assayed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoblotting. IFN-α was estimated in the sera by an ELISA method. Poly I:C injection induced IFN-α.Mononuclear cells were detected at the portal areas 8 weeks after the start of poly I:C injection, which progressed up to 16 weeks. Autoantibodies, including AMA, were detected in the sera from all poly I:C-injected mice.In conclusion, we show an early development of a PBC-like cholangitis in a genetically susceptible mouse strain because of poly I:C administration. This model would be helpful to study PBC immunopathogenesis and to evaluate the effectiveness of newly developed therapeutic regimens for PBC. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes that suppress the functions of antigen-presenting cells and effector T cells, characterized by the expression of transcription factor forkhead box P3 (FOXP3). Recent studies have reported an increase in the number of Tregs in the bone marrow (BM) of multiple myeloma (MM) patients. However, the role and mechanisms of Treg accumulation in the BM of MM patients remain debatable. Here, we present our data demonstrating the significance of Tregs in the context of MM disease progression. Using the transplantable MM mouse model, we observed a significant increase in Tregs in the BM of MM-injected mice from the early disease stage. We observed extended survival in MM-injected mice with Treg depletion than in mice without Treg depletion, demonstrating direct in vivo evidence that Tregs enhance disease progression in MM. It is noteworthy that type 1 interferon (IFN) signaling is activated in MM-associated Tregs. By using type 1 IFN receptor blocking antibody treatment and type 1 IFN receptor knockout Tregs, we demonstrated a significant decrease in MM-associated Treg proliferation, which was associated with longer survival in MM-injected mice. Thus, we have demonstrated that Tregs play a significant role in MM progression; the function and homeostasis of Tregs are regulated by type 1 IFN secreted in the BM microenvironment.

Purpose of Review: Mammalian orthoreovirus (reovirus) is a powerful tool for studying viral replication and pathogenesis. Most reovirus infections are subclinical, however recent work has catapulted reovirus into the clinical spotlight., Recent Findings: Owing to its capacity to kill cancer cells more efficiently than normal cells, reovirus is under development as a therapeutic for a variety of cancers. New efforts have focused on genetically engineering reovirus to increase its oncolytic capacity, and determining how reovirus potentiates immunotherapy. Other recent studies highlight a potential role for reovirus in celiac disease (CeD). Using mouse models of CeD, reovirus caused loss of oral tolerance to dietary antigens, opening the possibility that reovirus could trigger CeD in humans., Summary: We will focus on new developments in reovirus oncolysis and studies suggesting a role for reovirus as a trigger for celiac disease (CeD) that make reovirus a potential friend and foe to human health., Competing Interests: Conflict of Interest Michael R. Eledge, Marcelle Dina Zita, and Karl W. Boehme each declare no potential conflicts of interest.

Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.