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This study investigated the effects of chronic low-dose-rate radiation exposure on gene expression related to immunological defense mechanisms and epigenetic regulation in the testis of male mice. The study found that radiation exposure (4.5 mGy/hr until 4000 mGy) led to a significant decrease in the expression of genes involved in epigenetic regulation and a significant increase in the expression of several genes linked to innate and acquired immunity, suggesting a noticeable effect on the immune response. In addition, there was a significant increase in the expression of SRY-box transcription factor 9, which plays a crucial role in testicular development, indicating a response to irradiation. These findings provide insights into the biological effects of chronic low-dose-rate radiation exposure on innate immunity and epigenetic regulation in the testis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy., (© 2024 Wang et al.)

Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 10 8  CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland., (© 2021 The Pathological Society of Great Britain and Ireland.)

Mitochondrial antiviral signaling (MAVS) protein mediates innate antiviral responses, including responses to certain coronaviruses such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We have previously shown that ultraviolet-A (UVA) therapy can prevent virus-induced cell death in human ciliated tracheal epithelial cells (HTEpC) infected with coronavirus-229E (CoV-229E), and results in increased intracellular levels of MAVS. In this study, we explored the mechanisms by which UVA light can activate MAVS, and whether local UVA light application can activate MAVS at locations distant from the light source (e.g. via cell-to-cell communication). MAVS levels were compared in HTEpC exposed to 2 mW/cm 2 narrow band (NB)-UVA for 20 min and in unexposed controls at 30-40% and at 100% confluency, and in unexposed HTEpC treated with supernatants or lysates from UVA-exposed cells or from unexposed controls. MAVS was also assessed in different sections of confluent monolayer plates where only one section was exposed to NB-UVA. Our results showed that UVA increases the expression of MAVS protein. Further, cells in a confluent monolayer exposed to UVA conferred an elevation in MAVS in cells adjacent to the exposed section, and also in cells in the most distant sections which were not exposed to UVA. In this study, human ciliated tracheal epithelial cells exposed to UVA demonstrate increased MAVS protein, and also appear to transmit this influence to confluent cells not exposed to UVA, likely via cell-cell signaling., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Radiation therapy, which is vital for the treatment of primary liver cancer, comes with unavoidable liver injury, which limits its implementation. N6-methyladenosine (m6A) methylation is involved in many molecular functions. However, its role in radiation-induced liver diseases (RILD) remains unknown. Herein, we investigate the role of m6A methylation in RILD., Methods and Materials: Methylated RNA-immunoprecipitation sequencing and RNA transcriptome sequencing were used to reveal the methylation pattern of human hepatic stellate cells (HSCs) exposed to irradiation. C3H/HeN mice and stimulator of interferon genes (STING)-deficient mice underwent x-ray irradiation of 24 Gy in 3 fractions. The m6A methylation of the high-mobility group box 1 (HMGB1) transcript was validated using methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase assays, and a messenger RNA decay assay., Results: Human hepatic stellate cells showed significant differences in methylation patterns after 8 Gy of x-ray irradiation. Irradiation recruited AlkB homolog 5 (ALKBH5) to demethylate m6A residues in the 3' untranslated region of HMGB1, which resulted in the activation of STING-interferon regulatory factor 3 signaling. Changes in the transcription of the 3' untranslated region of HMGB1 occurred after the knockdown of ALKBH5, which were eliminated after m6A residue mutation. Strikingly, ALKBH5 deficiency or HMGB1 silencing both attenuated type I interferon production and decreased hepatocyte apoptosis. In vivo depletion of ALKBH5 abolished the upregulation of HMGB1-mediated STING signaling and decreased liver inflammation, which was consistent with STING -/- mice treated with irradiation. Notably, YTHDF2 (m6A reader protein) directly bound to HMGB1 m6A-modified sites and promoted its degradation., Conclusions: ALKBH5-dependent HMGB1 expression mediates STING-interferon regulatory factor 3 innate immune response in RILD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT)., Methods and Materials: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or -depleting agents. Tumor growth was monitored as a readout of therapeutic response. Flow cytometry and RNA sequencing of mouse tumors and analysis of transcriptomic data sets from irradiated human cancers were used to examine the immunomodulatory effects of the different radiation schedules., Results: In AT3-OVA tumors, radiation DPF rather than BED determined the ability of RT to evoke local antitumor CD8 + T cell responses and synergize with anti-PD-1 therapy. Natural killer cell-mediated control of irradiated tumors was more sensitive to radiation BED. Radiation-induced regulatory T cell (Treg) responses, which were detected in both mouse and human tumors, were a major factor underlying the differential activation of adaptive immunity by radiation DPF and the activity of natural killer cells during the early phase of response to RT. Targeted inhibition of Treg responses within irradiated tumors rescued and enhanced local tumor control by RT and permitted the generation of abscopal and immunologic memory responses, irrespective of radiation schedule. MC38 tumors did not support the induction of an amplified Treg response to RT and were highly vulnerable to its immunoadjuvant effects., Conclusions: Local radiation-induced Treg responses are influenced by radiation schedule and tumor type and are a critical determinant of the immunoadjuvant potential of RT and its ability to synergize with T cell-targeted immunotherapy., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microglia, the innate immune cells of the central nervous system, play a pivotal role in the modulation of neuroinflammation. Neuroinflammation has been implicated in many diseases of the CNS, including Alzheimer's disease and Parkinson's disease. It is well documented that microglial activation, initiated by a variety of stressors, can trigger a potentially destructive neuroinflammatory response via the release of pro-inflammatory molecules, and reactive oxygen and nitrogen species. However, the potential anti-inflammatory and neuroprotective effects that microglia are also thought to exhibit have been under-investigated. The application of ionising radiation at different doses and dose schedules may reveal novel methods for the control of microglial response to stressors, potentially highlighting avenues for treatment of neuroinflammation associated CNS disorders, such as Alzheimer's disease and Parkinson's disease. There remains a need to characterise the response of microglia to radiation, particularly low dose ionising radiation.

Zinc oxide nanoparticles (ZnO-NPs) are widely used in almost every area of life. Therefore, exposure to them is unavoidable, which makes it necessary to assess their safety for humans. This paper aims to determine toxicity of ZnO-NPs of two diameters toward human immune cells responsible for: innate response (U-937 and HL-60) and acquired response (COLO-720L and HUT-78). Mitochondrial activity, membrane integrity, degree of cellular lipid oxidation, induction of inflammation, and activation of the apoptosis pathway were evaluated to determine differences in cellular response to the tested nanoparticles. ZnO-NPs with a diameter of 100 and 130 nm cause significant cell mortality at 25 and 12 mg/L, respectively. Mitochondrial damage leads to the activation of the caspase cascade and, consequently, to cell apoptosis. ZnO-NPs also cause peroxidation of membrane lipids. Due to the photocatalytic properties of ZnO-NPs, the effect of ultraviolet (UV) irradiation on the degree of their toxicity was also investigated. However, UV irradiation enhances the toxic effect of nanoparticles mainly by weakening the cell's defense capabilities. ZnO-NPs are cytotoxic to human immune system, and they may cause both long-term and short-term negative effects., (© 2020 John Wiley & Sons, Ltd.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become pandemic on March 11 th , 2020. COVID-19 has a range of symptoms that includes fever, fatigue, dry cough, aches, and labored breathing to acute respiratory distress and possibly death. Health systems and hospitals have been completely rearranged since March 2020 in order to limit the high rate of virus spreading. Hence, a great debate on deferrable visits and treatments including phototherapy for skin diseases is developing. In particular, as regards phototherapy very few data are currently available regarding the chance to continue it, even if it may be a useful resource for treating numerous dermatological patients. However, phototherapy has an immunosuppressive action possibly facilitating virus infection. In the context of COVID-19 infection risk it is important to pointed out whether sunlight, phototherapy and in particular ultraviolet radiation (UV-R) constitute or not a risk for patients. In this review we aimed to focus on the relationship between UV-R, sunlight, phototherapy, and viral infections particularly focusing on COVID-19.

In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 - as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co 60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 μg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.

Abscopal effects are an important aspect of targeted radiation therapy due to their implication in normal tissue toxicity from chronic inflammatory responses and mutagenesis. Gene expression can be used to determine abscopal effects at the molecular level. Synchrotron microbeam radiation therapy utilizing high-intensity X rays collimated into planar microbeams is a promising cancer treatment due to its reported ability to ablate tumors with less damage to normal tissues compared to conventional broadbeam radiation therapy techniques. The low scatter of synchrotron radiation enables microbeams to be delivered to tissue effectively, and is also advantageous for out-of-field studies because there is minimal interference from scatter. Mouse legs were irradiated at a dose rate of 49 Gy/s and skin samples in the out-of-field areas were collected. The out-of-field skin showed an increase in Tnf expression and a decrease in Mdm2 expression, genes associated with inflammation and DNA damage. These expression effects from microbeam exposure were similar to those found with broadbeam exposure. In immune-deficient Ccl2 knockout mice, we identified a different gene expression profile which showed an early increase in Mdm2, Tgfb1, Tnf and Ccl22 expression in out-of-field skin that was not observed in the immune-proficient mice. Our results suggest that the innate immune system is involved in out-of-field tissue responses and alterations in the immune response may not eliminate abscopal effects, but could change them., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS-STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS-STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer-highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS-STING signaling, deleterious effects associated with cGAS-STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS-STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

Objective: To assess the role of CCR10 in innate lymphoid cells (ILCs) response in radiation-induced skin damage., Material and Methods: CCR10 +/- and CCR10 -/- mice were treated with either a single dose of 5 Gy or 5 Gy everyday for 6 days with a total dose of 30 Gy with X-ray. ILCs from the skin were isolated and analyzed by flow cytometry 3 and 10 days after irradiation. A mouse model of radio-dermatitis was used to assess the skin damage 10 days after 6 × 5 Gy irradiation., Results: Skin ILCs were decreased in both CCR10 +/- and CCR10 -/- mice 3 days after single irradiation ( p  < .05). However, the skin inflammation disappeared and ILCs returned to normal levels 10 days after single irradiation. ILCs of both genotypes were also decreased after 6 × 5 Gy irradiation, but the percentage of skin ILCs in CCR10 -/- mice was lower than that in CCR10 +/- mice 10 days after irradiation. The immunohistochemistry results showed that CCR10 -/- mice had more severe skin inflammation than CCR10 +/- mice., Conclusion: CCR10 -/- mice had lower percentages of ILCs and more skin damage than CCR10 +/- mice after irradiation. These findings indicate that skin ILCs are regulated by CCR10, which might be a potential target for reducing the radio-dermatitis.

Radiotherapy is a pivotal component in the curative treatment of patients with localised cancer and isolated metastasis, as well as being used as a palliative strategy for patients with disseminated disease. The clinical efficacy of radiotherapy has traditionally been attributed to the local effects of ionising radiation, which induces cell death by directly and indirectly inducing DNA damage, but substantial work has uncovered an unexpected and dual relationship between tumour irradiation and the host immune system. In clinical practice, it is, therefore, tempting to tailor immunotherapies with radiotherapy in order to synergise innate and adaptive immunity against cancer cells, as well as to bypass immune tolerance and exhaustion, with the aim of facilitating tumour regression. However, our understanding of how radiation impacts on immune system activation is still in its early stages, and concerns and challenges regarding therapeutic applications still need to be overcome. With the increasing use of immunotherapy and its common combination with ionising radiation, this review briefly delineates current knowledge about the non-targeted effects of radiotherapy, and aims to provide insights, at the preclinical level, into the mechanisms that are involved with the potential to yield clinically relevant combinatorial approaches of radiotherapy and immunotherapy.

Vesicular stomatitis virus (VSV) expressing IFNβ induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNβ is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNβ (hIFNβ) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective when used in combination with radiotherapy (RT). We investigated the synergistic effects of RT and VSV-hIFNβ in the subcutaneous PC3 and orthotopic LNCaP prostate xenograft models and a syngeneic RM9 prostate tumor model. VSV-IFNβ combined with RT amplified tumor killing for PC3 and LNCaP xenografts, and RM9 tumors. This was attributed to the induction of proapoptotic genes leading to increased VSV-IFNβ infection and replication, VSV expression, and oncolysis. In the RM9 tumors, combination therapy resulted in a robust antitumor immune response. Treated RM9 tumor-bearing mice demonstrated an increase in CD8 + and CD4 + T-cell numbers, 100% resistance to tumor rechallenge, and reduced resistance to reimplantation challenge with CD8 + knockdown. RT enhanced the activity of VSV-mediated oncolysis via attenuation of the innate antiviral response, resulting in increased VSV replication and the generation of an adaptive immune response earmarked by an increase in CD8 + lymphocyte numbers and antitumor activity. Local tumor irradiation combined with VSV-IFNβ affects tumor cell death through direct and systemic activity in conjunction with pronounced antitumor immunity. IMPLICATIONS: Radiotherapy enhances VSV-mediated oncolysis and anti-tumor immunity, indicating that the ombination has promise for very high risk prostate cancer., (©2020 American Association for Cancer Research.)

Functional circadian timekeeping is necessary for homeostatic control of the immune system and appropriate immune responsiveness. Disruption of natural light-dark cycles, through light at night (LAN), impairs innate and adaptive immune responses in nocturnal rodents. These altered immune responses are associated with disrupted endogenous gene transcriptional and endocrine cycles. However, few studies have addressed the multigenerational consequences of systemic circadian rhythm disruption. We hypothesized that parental exposure to dim LAN (dLAN) would alter innate immune and sickness responses to an endotoxin challenge in adult offspring gestated and reared in dark nights. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 8 weeks, then paired, mated, and thereafter housed under dark nights. Maternal exposure to dLAN prior to conception impaired febrile responses and increased splenic il-1 production in response to LPS in male offspring. Paternal pre-conception dLAN dampened offspring tnf-α expression in the hypothalamus, reduced serum bactericidal capacity, and dark phase locomotor activity. These changes occurred despite offspring being conceived, gestated, and reared under standard dark night conditions. Overall, these data suggest that dLAN has intergenerational effects on innate immunity and sickness responses., Competing Interests: The authors have declared that no competing interests

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.

The role of radiation therapy for cancer is evolving as its biologic effects on tumors becomes more clearly defined. Traditionally, radiobiology models dose-response curves based on direct cytocidal effects of radiation on tumor cells. However, a more dynamic picture is emerging of the impact of radiation on the tumor microenvironment and the patient's innate and adaptive immune system. Radiation produces damage associated molecular patterns that activate innate immune receptors leading to a cascade of downstream signals. These signals alter the tumor infiltrating immune population, modulate immune cell activation status, and enhance antigen presentation. The changes are conducive to an adaptive immune response with the generation of antitumor T cells. Early findings from clinical trials incorporating radiation and immune checkpoint inhibitors show promising synergy between the 2 modalities. As more data matures from ongoing trials, clinicians can refine new strategies for using radiation together with immunotherapy to achieve improved clinical outcomes., (Copyright © 2019. Published by Elsevier Inc.)

A malignant tumor consists of malignant cells as well as a wide array of normal host tissues including stroma, vasculature, and immune infiltrate. The interaction between cancer and these host tissues is critical as these host tissues play a variety of roles in supporting or resisting disease progression. Radiotherapy (RT) has direct effects on malignant cells, but, also, critically important effects on these other components of the tumor microenvironment (TME). Given the growing role of immune checkpoint inhibitors and other immunotherapy strategies, understanding how RT affects the TME, particularly the immune compartment, is essential to advance RT in this new era of cancer therapy. The interactions between RT and the TME are complex, affecting the innate and adaptive arms of the immune system. RT can induce both proinflammatory effects and immune suppressive effects that can either promote or impede antitumor immunity. It is likely that the initial proinflammatory effects of RT eventually lead to rebound immune-suppression as chronic inflammation sets in. The exact kinetics and nature of how RT changes the TME likely depends on timing, dose, fractionation, site irradiated, and tumor type. With increased understanding of the effects of RT on the TME, in the future it is likely that we will be able to personalize RT by varying the dose, site, and timing of intervention to generate the desired response to partner with immunotherapy strategies., (Copyright © 2019. Published by Elsevier Inc.)

The anti-tumor activity of interferons (IFNs) was first appreciated about half a century ago, and IFN-α2 was the first cancer immunotherapy approved by the US Food and Drug Administration. Radiation therapy (RT), one of the pillars of cancer treatment, directly causes DNA damage, which can lead to senescence and cell death in tumor cells. In recent years, however, RT-induced immunomodulatory effects have been recognized to play an indispensable role in achieving the optimum therapeutic effect of RT. Increasing evidence indicates that RT enhances adaptive anti-tumor immunity by augmenting the innate immune sensing of tumors in a type I IFN-dependent matter. This review briefly introduces the role of type I interferon in cancer and the available evidence on the overall effects of RT on tumor immunity mediated via type I IFN. Recent advances in deciphering the molecular mechanisms underlying the induction of type I IFNs triggered by RT, their clinical implications, and therapeutic opportunities will be highlighted., (Published by Elsevier Inc.)

Along with rapid offshore and onshore wind power development in modern society, extremely low frequency electromagnetic fields (ELF-EMF) is produced extensively in the habits of aquatic organisms. However, the biological effects of ELF-EMF on aquatic organisms are almost sparse. In this study, Onchidium struma without shell was chosen to aim whether ELF-EMF can elicit immune response of mollusk based on immune-related enzyme activities and gene expression through high-throughput transcriptome sequencing. Three experimental groups, i.e. ELF-EMF unexposed control group (C), ELF-EMF (50 Hz, 100 μT) exposed E1 group, and ELF-EMF (50 Hz, 500 μT) exposed E2 group, were set, and coelomocytes were collected to analyze. The results showed that total coelomocyte and spherulocyte density in E1 group increased significantly compared to groups C and E2 (P < 0.05). There were no significant differences on amoebocyte and chromatocyte density among groups C, E1 and E2. ELF-EMF exposure could significantly increase immune-related enzyme activities in coelomic fluid of O. struma, including acidic phosphatase, alkaline phosphatase, antioxidative capacity, catalase, superoxide dismutase, and polyphenol oxidase (P < 0.05). A total of 54.32 Mb and 55.27 Mb raw reads with average length of 1520 bp were obtained from coelomocytes of O. struma in unexposed and exposed groups, respectively. There were 341 differentially expressed genes (DGEs) between unexposed and exposed groups, including 209 up-regulated and 132 down-regulated unigenes. All the DGEs were allocated to 14 Kyoto Encyclopedia of Genes and Genomes pathways, and five pathways were associated with immune response, including TLR/TNF/NOD-like receptor/MAPK/Fc epsilon RI signaling pathways. Altogether, short-term (to one week) exposure of O. struma to lower luxy density ELF-EMF (<500 μT) could elicit the immune response, and antioxidant system is recommended as indicators of immunological effects. Hopefully, this study will further provide insights into exploring biomarker for evaluation of the effect of ELF-EMF exposure on aquatic organisms regarding to field density, frequency and exposure duration, and provide good guidance for exploitation and utilization of renewable energy., Competing Interests: Declaration of competing interest The research was conducted in the absence of any commercial or financial relationships. We declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist muramyl dipeptide (MDP), a peptidoglycan motif common to all bacteria, supports leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) + intestinal stem cell (ISC) survival through NOD2 activation upon an otherwise lethal oxidative stress-mediated signal. However, the underlying protective mechanisms remain unknown. Here, using irradiation as stressor and primarily murine-derived intestinal organoids as a model system, we show that MDP induced a significant reduction of total and mitochondrial reactive oxygen species (ROS) within ISCs, which was associated with mitophagy induction. ATG16L1 knockout (KO) and NOD2 KO organoids did not benefit from the MDP-induced cytoprotection. We confirmed the MDP-dependent induction of ISC mitophagy upon stress in vivo. These findings elucidate the NOD2-mediated mechanism of cytoprotection involving the clearance of the lethal excess of ROS molecules through mitophagy, triggered by the coordinated activation of NOD2 and ATG16L1 by a nuclear factor κB (NF-κB)-independent pathway., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Rationale: Glioblastoma is the most frequent, primary brain tumor that is characterized by a highly immunosuppressive tumor microenvironment (TME). The TME plays a key role for tumor biology and the effectiveness of immunotherapies. Composition of the TME correlates with overall survival and governs therapy response. Non invasive assessment of the TME has been notoriously difficult. Methods: We have designed an in vivo imaging approach to non invasively visualize innate immune cell dynamics in the TME in a mouse glioma model by correlated MRI and multiphoton microscopy (MR-MPM) using a bimodal, fluorescently labeled iron oxide nanoparticle (NP). The introduction of Teflon cranial windows instead of conventional Titanium rings dramatically reduced susceptibility artifacts on MRI and allowed longitudinal MR-MPM imaging for innate immune cell tracking in the same animal. Results: We visualized tumor associated macrophage and microglia (TAM) dynamics in the TME and dissect the single steps of NP uptake by blood-born monocytes that give rise to tumor-associated macrophages. Next to peripheral NP-loading, we identified a second route of direct nanoparticle uptake via the disrupted blood-brain barrier to directly label tissue resident TAMs. Conclusion: Our approach allows innate immune cell tracking by MRI and multiphoton microscopy in the same animal to longitudinally investigate innate immune cell dynamics in the TME., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction : Environmental factors and an altered fecal microbiome are believed to be central to the pathogenesis of inflammatory bowel diseases (IBD). Vitamin D and ultraviolet radiation (UVR) are environmental factors that are associated by several pathways, including changes to the gastrointestinal microbiome, with the development and course of IBD. Area covered : This review explores the interaction of vitamin D, and UVR, with the intestinal innate and adaptive immune systems, and how they may influence the gut microbiome and the subsequent development, and progression, of IBD. Expert opinion : Vitamin D and UVR both regulate innate and adaptive immunity through a combination of common and independent mechanisms, with the overall effect being the promotion of immune tolerance. Vitamin D, and to a lesser extent UVR, can modify the gastrointestinal microbiome either directly, or through immune-mediated mechanisms and this may explain the effect on intestinal inflammation in animal models of IBD and some clinical studies. Thus, both vitamin D and UVR exposure can be considered potential 'master regulators' of gastrointestinal immunity, fine-tuning the complex interaction between genetics, host immunity and the gut microbiome. Further research and increased understanding of environment-host interactions is essential to achieving the ultimate goal of preventing and curing IBD.

Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism 1 . ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence 2,3 . Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.

Sensory neurons promote profound suppressive effects on neutrophils during Streptococcus pyogenes infection and contribute to the pathogenesis of necrotizing infection ("flesh-eating disease"). Thus, the development of new antibacterial agents for necrotizing infection is promising because of the clear streptococcal neuro-immune communication. Herein, based on the immune escape membrane exterior and competitive membrane functions of the glioma cell membrane, a novel nano neuro-immune blocker capsule was designed to prevent neuronal activation and improve neutrophil immune responses for necrotizing infection. These nano neuro-immune blockers could neutralize streptolysin S, suppress neuron pain conduction and calcitonin gene-related peptide release, and recruit neutrophils to the infection site, providing a strong therapeutic effect against necrotizing infection. Furthermore, nano neuro-immune blockers could serve as an effective inflammatory regulator and antibacterial agent via photothermal effects under near-infrared irradiation. In the Streptococcus pyogenes -induced necrotizing fasciitis mouse model, nano neuro-immune blockers showed significant therapeutic efficacy by ameliorating sensitivity to pain and promoting the antibacterial effect of neutrophils.

Radiotherapy to treat brain tumors can potentially harm the central nervous system (CNS). The radiation stimulates a series of immune responses in both the CNS as well as peripheral immune system. To date, studies have mostly focused on the changes occurring in the immune response within the CNS. In this study, we investigated the effect of γ-ray-induced CNS injury on the peripheral immune response using a cell co-culture model and a whole-brain irradiation (WBI) rat model. Nerve cells (SH-SY5Y and U87 MG cells) were γ-ray irradiated, then culture media of the irradiated cells (conditioned media) was used to culture immune cells (THP-1 cells or Jurkat cells). Analyses were performed based on the response of immune cells in conditioned media. Sprague-Dawley rats received WBI at different doses, and were fed for one week to one month postirradiation. Spleen and peripheral blood were then isolated and analyzed. We observed that the number of monocytes in peripheral blood, and the level of NK cells and NKT cells in spleen increased after CNS injury. However, the level of T cells in spleen did not change and the level of B cells in the spleen decreased after γ-ray-induced CNS injury. These findings indicate that CNS injury caused by ionizing radiation induces a series of changes in the peripheral immune system.

Humans have greatly altered Earth's night-time photic environment via the production of artificial light at night (ALAN; e.g. street lights, car traffic, billboards, lit buildings). ALAN is a problem of growing importance because it may significantly disrupt the seasonal and daily physiological rhythms and behaviors of animals. There has been considerable interest in the impacts of ALAN on health of humans and other animals, but most of this work has centered on adults and we know comparatively little about effects on young animals. We exposed 3-week-old king quail (Excalfactoria chinensis) to a constant overnight blue-light regime for 6 weeks and assessed weekly bactericidal activity of plasma against Escherichia coli - a commonly employed metric of innate immunity in animals. We found that chronic ALAN exposure significantly increased bactericidal activity and that this elevation in immune performance manifested at different developmental time points in males and females. Whether this short-term increase in immune activity can be extended to wild animals, and whether ALAN-mediated increases in immune activity have positive or negative fitness effects, are unknown and will provide interesting avenues for future studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Light is a key environmental factor that synchronizes various life stages from embryo development to sexual maturation in fish. For turbot, light spectra have the most influence at the larval and juvenile stages. In the current study, differences in the development of embryos and the performance of newly hatched turbot larvae exposed to five different spectra: full spectrum (LDF), blue (LDB, peak at 450 nm), green (LDG, peak at 533 nm), orange (LDO, peak at 595 nm) and red (LDR, peak at 629 nm), were examined. At 62.8 h post fertilization, a higher number of embryos exposed to short-wavelengths (LDG and LDB) had developed a heartbeat in comparison with embryos exposed to other wavelengths. Larvae exposed to the green spectrum had higher malformation rates than larvae exposed to the other spectra, indicating that larvae exposed to green light may have significantly reduced survival rates. The results of non-specific immunity parameters showed that the mRNA expression levels of cathepsin D (CTSD), cathepsin F (CTSF), catalase (CAT) and metallothionein (MT) in larvae exposed to LDB were significantly higher than those exposed to other spectra, but CAT activity in larvae exposed to LDB was significantly lower than larvae exposed to the other spectra. There was no significant difference in MT activity in larvae exposed to the five different spectra. The mRNA expression level of lysozyme (LZM) in larvae exposed to LDR was significantly higher than other spectra, while there was no significant difference in LZM activity observed in larvae exposed to LDR, LDG, LDB and LDF. The difference of the enzyme activity of total superoxide dismutase (T-SOD) was not significant among larvae exposed to the five spectra. mRNA expression of the heat shock protein 70 (HSP70) was significantly higher in newly hatched larvae exposed to LDB, LDR and LDG, indicating that larvae exposed to LDB, LDG and LDR exhibited a stress response. The mRNA expression level of the insulin-like growth factor-1 (IGF-1) and growth parameters in the newly hatched larvae exposed to the different spectra were not significantly different. The results of the present study indicate that LDO and LDF should be used for embryo incubation and newly hatched larvae when rearing turbot. This study provides a theoretical basis for optimizing the incubation light environment for fertilized turbot eggs, promoting immunity and reducing stress responses in newly hatched larvae., (Copyright © 2019. Published by Elsevier Ltd.)

Fluorescent light (FL) has been utilized for ≈60 years and has become a common artificial light source under which animals, including humans, spend increasing amounts of time. Although the solar spectrum is quite dissimilar in both wavelengths and intensities, the genetic consequences of FL exposure have not been investigated. Herein, we present comparative RNA-Seq results that establish expression patterns within skin, brain, and liver for Danio rerio , Oryzias latipes , and the hairless mouse ( Mus musculus ) after exposure to FL. These animals represent diurnal and nocturnal lifestyles, and ≈450 million years of evolutionary divergence. In all three organisms, FL induced transcriptional changes of the acute phase response signaling pathway and modulated inflammation and innate immune responses. Our pathway and gene clustering analyses suggest cellular perception of oxidative stress is promoting induction of primary up-stream regulators IL1B and TNF . The skin and brain of the three animals as well as the liver of both fish models all exhibit increased inflammation and immune responses; however, the mouse liver suppressed the same pathways. Overall, the conserved nature of the genetic responses observed after FL exposure, among fishes and a mammal, suggest the presence of light responsive genetic circuitry deeply embedded in the vertebrate genome., Competing Interests: The authors declare no competing interests.

Radiation continues to play a major role in the treatment of almost every cancer type. Traditional radiation studies focused on its ability to damage DNA, but recent evidence has demonstrated that a key mechanism driving the efficacy of radiation in vivo is the immune response triggered in irradiated tissue. Innate immune cells including macrophages, dendritic cells, and natural killer cells are key mediators of the radiation-induced immune response. They regulate the sensing of radiation-mediated damage and subsequent radiation-induced inflammation. Given the importance of innate immune cells as determinants of the post-radiation anti-tumor immune response, much research has been devoted to identify ways to both enhance the innate immune response and prevent their ability to suppress ongoing immune responses. In this review, we will discuss how the innate immune system shapes anti-tumor immunity following radiation and highlight key strategies directed at the innate immune response to enhance the efficacy of radiation.

Arabidopsis thaliana and Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) comprise an effective model pathosystem for resolving mechanisms behind numerous aspects of plant innate immunity. Following the characterization of key molecular components over the past decades, we may begin investigating defense signaling under various environmental conditions to gain a more holistic understanding of the underlying processes. As a critical regulator of growth and development, exploration into the influence of light on pathogenesis is a logical step toward a systems-level understanding of innate immunity. Based on methods described previously, here we describe a method for investigating plant immune responses under various light environments.

Extremely low frequency electromagnetic field (ELF-EMF) is produced extensively in modern technologies. Numerous in vitro and in vivo studies have shown that ELF-EMF has both stimulatory and inhibitory effects on the immune system response. This review was conducted on effects of ELF-EMF on cytokines of innate and adaptive immunity. Mechanisms of ELF-EMF, which may modulate immune cell responses, were also studied. Physical and biological parameters of ELF-EMF can interact with each other to create beneficial or harmful effect on the immune cell responses by interfering with the inflammatory or anti-inflammatory cytokines. According to the studies, it is supposed that short-term (2-24 h/d up to a week) exposure of ELF-EMF with strong density may increase innate immune response due to an increase of innate immunity cytokines. Furthermore, long-term (2-24 h/d up to 8 years) exposure to low-density ELF-EMF may cause a decrease in adaptive immune response, especially in T h 1 subset.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

In cancer treatments, especially high-dose radiotherapy (HDRT) is applied. Patients suffering from chronic inflammatory diseases benefit from low-dose radiation therapy (LDRT), but exposure to very low radiation doses can still steadily increase for diagnostic purposes. Yet, little is known about how radiation impacts on forms of cell death in human immune cells. In this study, the radiosensitivity of human immune cells of the peripheral blood was examined in a dose range from 0.01 to 60 Gy with regard to induction of apoptosis, primary necrosis, and secondary necrosis. Results showed that immune cells differed in their radiosensitivity, with monocytes being the most radioresistant. T cells mainly died by necrosis and were moderately radiosensitive. This was followed by B and natural killer (NK) cells, which died mainly by apoptosis. X-radiation had no impact on cell death in immune cells at very low doses (≤0.1 Gy). Radiation doses of LDRT (0.3⁻0.7 Gy) impacted on the more radiosensitive NK and B cells, which might contribute to attenuation of inflammation. Even single doses applied during RT of tumors did not erase the immune cells completely. These in vitro studies can be considered as the basis to optimize individual radiation therapy schemes in multimodal settings and to define suited time points for further inclusion of immunotherapies.

Astronauts on missions beyond low-Earth orbit are exposed to a hostile environment in which they are continually bombarded with unique high-energy species of radiation, while in conditions of microgravity (μG), which can alter radiation response and immunity. In the present studies, we examined the impact exposing human hematopoietic stem/progenitor cells (HSC) to μG had upon their capacity to repair DNA damage and their ability to generate immune cells critical for mounting an effective antitumor response. To this end, we first treated a human HSC-like cell line with an acute dose of the radiomimetic drug bleomycin, cultured them in normal gravity (1G) or simulated μG, and quantitated double-strand breaks through γ-H2AX foci. Calculating the median fluorescence intensity ratio at 1-to-4 h post-bleomycin revealed a 26% decrease in 1G, but a 20% increase in μG, suggesting that μG compromised HSC DNA damage repair and thus has the potential to enhance the genotoxic effects of space radiation. We next examined whether μG negatively affected the development of dendritic cells (DC), critical regulators of both the innate and acquired arms of the immune system. Primary human HSC were cytokine induced in 1G or μG and analyzed for generation of plasmacytoid (CD123 + ) and myeloid (CD11c + ) DC. HSC cultured in 1G gave rise to significantly higher numbers of both myeloid and plasmacytoid DC than those cultured in μG, suggesting μG impairs production of these critical antigen-presenting cells. Our studies thus indicate that conditions of μG present during spaceflight perturb multiple pathways that could potentially enhance astronaut risk from exposure to space radiation.

Purpose: A well-known phenomenon in the field of radiation biology is that cells exposed to ionizing radiation (IR) (targeted cells) can induce in non-irradiated (non-targeted), bystander cells effects reminiscent of DNA damage responses (DDR) normally expected, exclusively in targeted cells. These phenomena are collectively referred to as radiation-induced bystander effects (RIBE) and have different manifestations depending on the endpoint studied. Although it is now recognized that RIBE reflects to a considerable extent communication by the targeted cells to undamaged cells of their damaged status, the molecular underpinnings of this communication and its significance for the organism are only partly understood. In particular, it remains unknown why and how targeted cells induce DNA damage in non-targeted, bystander cells threatening their genomic stability and risking thus their transformation to cancer cells. Here, we outline observations hinting to possible sources of artifacts in experiments designed to detect RIBE and summarize a model according to which targeted cells modulate their redox status as part of their overall response to IR and use this modified redox status as a source to generate signals that are transmitted to non-irradiated cells of the organism., Material and Methods: A synthesis of published evidence is presented., Results: Depending on type, RIBE signals may be transmitted through various forms of direct intercellular contact, through molecules acting locally in a paracrine fashion, or through molecules acting remotely in an endocrine fashion. We reason that DNA damage generated in bystander cells is unlikely to manifest the clustered character exhibited in directly exposed cells and postulate that RIBE will depend on complications generated when simpler forms of damage encounter the DNA replication fork., Conclusions: We suggest that RIBE result from intercellular communication mechanisms designed to spread within tissues, or the organism, alarm signals of DNA damage inflicted in subsets of the constituent cells. This response likely evolved to protect organisms by appropriately modulating stress response, repair or apoptosis, and may in some instances also cause adverse effects, e.g. as collateral damage.

Tritium is a potentially significant source of internal radiation exposure which, at high levels, can be carcinogenic. We evaluated whether single intraperitoneal injection of BALB/c and C57BL/6 mice with tritiated water (HTO) leading to exposure to low (0.01 or 0.1 Gy) and intermediate (1.0 Gy) cumulative whole-body doses of β radiation is immunosuppressive, as judged by enhancement of artificial tumour metastases, functioning of NK lymphocytes and macrophages, circulating cytokine's levels, and numbers of bone marrow, spleen, and peripheral blood cells. We demonstrate that internal contamination of radiosensitive BALB/c and radioresistant C57BL/6 mice with HTO at all the absorbed doses tested did not affect the development of neoplastic colonies in the lungs caused by intravenous injection of syngeneic cancer cells. However, internal exposure of BALB/c and C57BL/6 mice to 0.1 and 0.01 Gy of β radiation, respectively, up-regulated cytotoxic activity of and IFN-γ synthesis in NK lymphocytes and boosted macrophage secretion of nitric oxide. Internal contamination with HTO did not affect the serum levels of pro- (IL-1β, IL-2, IL-6, TNF-α,) and anti-inflammatory (IL-1Ra, IL-4, IL-10) cytokines. In addition, exposure of mice of both strains to low and intermediate doses from the tritium-emitted β-particles did not result in any significant changes in the numbers of bone marrow, spleen, and peripheral blood cells. Overall, our data indicate that internal tritium contamination of both radiosensitive and radioresistant mice leading to low and intermediate absorbed β-radiation doses is not immunosuppressive but may enhance some but not all components of anticancer immunity.

Candida albicans is an opportunistic pathogen commensal in the oral cavity, vagina, and healthy skin. Common therapeutic options for fungal infections are topical or systemic antifungal drugs. Recently, in cutaneous pathologies, lasers and light-based treatments have emerged showing few contraindications and minimal side effects. The Q-switched (Nd-YAG) laser at a wavelength of 1064 nm has been shown to be useful in dermatology, dentistry, and some other medical specialties. It is used to treat onychomycoses, warts, and wounds and in some other treatments. We analyzed the effect of Q-switched (Nd-YAG) laser 1064 nm on human keratinocytes infected with C. albicans. In particular, we evaluated the effect of laser on invasiveness of C. albicans and on inflammatory and protective response of HaCaT cells infected. The results obtained did not show inhibitory, fungicidal, or fungistatic effects of laser on yeast; in addition, laser did not affect HaCaT vitality. HaCaT cells infected with C. albicans and irradiated with laser showed a reduction of invasiveness of TNF-α and IL8 gene expression and an increase of immunomodulatory cytokines such as TGFβ. Furthermore, laser induces a significant over-expression of HSP70B (heat shock protein) and of HBD-2 (Human β defensin-2) in HaCaT infected with C. albicans, compared to the untreated control. The use of Q-switched Nd:YAG laser in skin mycosis caused by C. albicans reduces yeast invasiveness in keratinocytes, downregulates inflammatory activities, and facilitates cytoprotection and antimicrobial defense. Our results offer a promising therapeutic strategy in the management of skin candidiasis, also in combination with conventional therapies.

In mammals, a master clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus, a region that receives input from the retina that is transmitted by the retinohypothalamic tract. The SCN controls the nocturnal synthesis of melatonin by the pineal gland that can influence the activity of the clock's genes and be involved in the inhibition of cancer development. On the other hand, in the literature, some papers highlight that artificial light exposure at night (LAN)-induced circadian disruptions promote cancer. In the present review, we summarize the potential mechanisms by which LAN-evoked disruption of the nocturnal increase in melatonin synthesis counteracts its preventive action on human cancer development and progression. In detail, we discuss: (i) the Warburg effect related to tumor metabolism modification; (ii) genomic instability associated with L1 activity; and (iii) regulation of immunity, including regulatory T cell (Treg) regulation and activity. A better understanding of these processes could significantly contribute to new treatment and prevention strategies against hormone-related cancer types.

Interferon alpha/beta (IFN-α/β) is a critical mediator of protection against most viruses, with host survival frequently impossible in its absence. Many studies have investigated the pathways involved in the induction of IFN-α/β after virus infection and the resultant upregulation of antiviral IFN-stimulated genes (ISGs) through IFN-α/β receptor complex signaling. However, other than examining the effects of genetic deletion of induction or effector pathway components, little is known regarding the functionality of these responses in intact hosts and whether host genetic or environmental factors might influence their potency. Here, we demonstrate that the IFN-α/β response against multiple arthropod-vectored viruses, which replicate over a wide temperature range, is extremely sensitive to fluctuations in temperature, exhibiting reduced antiviral efficacy at subnormal cellular temperatures and increased efficacy at supranormal temperatures. The effect involves both IFN-α/β and ISG upregulation pathways with a major aspect of altered potency reflecting highly temperature-dependent transcription of IFN response genes that leads to altered IFN-α/β and ISG protein levels. Discordantly, signaling steps prior to transcription that were examined showed the opposite effect from gene transcription, with potentiation at low temperature and inhibition at high temperature. Finally, we demonstrate that by lowering the temperature of mice, chikungunya arbovirus replication and disease are exacerbated in an IFN-α/β-dependent manner. This finding raises the potential for use of hyperthermia as a therapeutic modality for viral infections and in other contexts such as antitumor therapy. The increased IFN-α/β efficacy at high temperatures may also reflect an innate immune-relevant aspect of the febrile response. IMPORTANCE The interferon alpha/beta (IFN-α/β) response is a first-line innate defense against arthropod-borne viruses (arboviruses). Arboviruses, such as chikungunya virus (CHIKV), can infect cells and replicate across a wide temperature range due to their replication in both mammalian/avian and arthropod hosts. Accordingly, these viruses can cause human disease in tissues regularly exposed to temperatures below the normal mammalian core temperature, 37°C. We questioned whether temperature variation could affect the efficacy of IFN-α/β responses against these viruses and help to explain some aspects of human disease manifestations. We observed that IFN-α/β efficacy was dramatically lower at subnormal temperatures and modestly enhanced at febrile temperatures, with the effects involving altered IFN-α/β response gene transcription but not IFN-α/β pathway signaling. These results provide insight into the functioning of the IFN-α/β response in vivo and suggest that temperature elevation may represent an immune-enhancing therapeutic modality for a wide variety of IFN-α/β-sensitive infections and pathologies., (Copyright © 2018 Lane et al.)

Mast cells are immune cells that mature within the host tissue. The acquired phenotype is dictated by the tissue microenvironment, giving rise to diverse tissue-dependent phenotypes and functions. The lack of cellular models reflecting phenotypes found in vivo and important differences between human and rodent mast cells are obstacles to the understanding of their exact role in several pathophysiological processes. Studies published over the past few years showed that mast cells' role lies far beyond their involvement in allergy and anaphylaxis. Studies demonstrating their participation in innate immune responses as well as tissue scaring and vascular pathologies allowed the understanding of their role in several diseases, but also gave contradictory results, especially concerning tissue response to ionizing radiations. Nevertheless, therapeutic tools exist to target mast cells, such as degranulation inhibitors, antihistamine, protease inhibitors or tyrosine kinase receptors antagonists, and may offer some interesting new therapeutic perspectives to manage acute and chronic after-effects of radiation therapy., (© 2018 médecine/sciences – Inserm.)

The natural nighttime environment is increasingly polluted by artificial light. Several studies have linked artificial light at night to negative impacts on human health. In free-living animals, light pollution is associated with changes in circadian, reproductive, and social behavior, but whether these animals also suffer from physiologic costs remains unknown. To fill this gap, we made use of a unique network of field sites which are either completely unlit (control), or are artificially illuminated with white, green, or red light. We monitored nighttime activity of adult great tits, Parus major, and related this activity to within-individual changes in physiologic indices. Because altered nighttime activity as a result of light pollution may affect health and well-being, we measured oxalic acid concentrations as a biomarker for sleep restriction, acute phase protein concentrations and malaria infection as indices of immune function, and telomere lengths as an overall measure of metabolic costs. Compared to other treatments, individuals roosting in the white light were much more active at night. In these individuals, oxalic acid decreased over the course of the study. We also found that individuals roosting in the white light treatment had a higher probability of malaria infection. Our results indicate that white light at night increases nighttime activity levels and sleep debt and affects disease dynamics in a free-living songbird. Our study offers the first evidence of detrimental effects of light pollution on the health of free-ranging wild animals., (© 2017 John Wiley & Sons Ltd.)

The circadian clock, which evolved to help organisms harmonize physiological responses to external conditions (such as the light/dark cycle, LD), is emerging as an important regulator of the immune response to infection. Gaining a complete understanding of how the circadian clock influences the immune cell response requires animal models that permit direct observation of these processes within an intact host. Here, we investigated the use of larval zebrafish, a powerful live imaging system, as a new model to study the impact of a fundamental zeitgeber, light, on the innate immune cell response to infection. Larvae infected during the light phase of the LD cycle and in constant light condition (LL) demonstrated enhanced survival and bacterial clearance when compared with larvae infected during the dark phase of the LD cycle and in constant dark condition (DD). This increased survival was associated with elevated expression of the zebrafish orthologues of the mammalian pro-inflammatory cytokine genes, Tumour necrosis factor-α, Interleukin-8 and Interferon-γ, and increased neutrophil and macrophage recruitment. This study demonstrates for the first time that the larval zebrafish innate immune response to infection is enhanced during light exposure, suggesting that, similar to mammalian systems, the larval zebrafish response to infection is light-regulated.

Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

Although T cell immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been well studied, long-term B cell immune reconstitution remains less characterized. We evaluated humoral immune reconstitution among 71 pediatric allo-HSCT recipients. Although tetanus toxoid antibody levels were normal at 1 year after allo-HSCT, antipolysaccharide carbohydrate antibodies remained persistently low for up to 5 years. While naive B cell counts normalized by 6 months, IgM memory B cell deficiency persisted for up to 2 years (P = .01); switched memory B cell deficiency normalized by 1 year after allo-HSCT. CD4 + T cell immune reconstitution correlated with that of switched memory B cells as early as 6 months after allo-HSCT (r = .55, P = .002) but did not correlate with IgM memory B cells at any time point after allo-HSCT. Taken together, this suggests that allo-HSCT recipients have impaired antibody immune reconstitution, mainly due to IgM memory B cell maturation block, compared with more prompt T cell-dependent switched memory cell immune reconstitution. We further explored other factors that might affect humoral immune reconstitution. The use of total body irradiation was associated with lower naive B cells counts at 6 months after HSCT (P = .04) and lower IgM (P = .008) and switched (P = .003) memory B cells up to 2 years. Allo-HSCT recipients with extensive chronic graft-versus-host disease had lower IgM memory B cell counts (P = .03) up to 2 years after allo-HSCT. The use of cord blood was associated with better naive (P = .01), IgM (P = .0005), and switched memory (P = .006) B cells immune reconstitution. These findings may inform future prophylaxis and treatment strategies regarding risk of overwhelming infection, graft-versus-host disease, and post-allogeneic HSCT revaccination., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Investigations into the interaction between radiotherapy and the host immune system have uncovered new mechanisms that can potentially be exploited to improve the efficacy of radiotherapy. Radiation promotes the release of danger signals and chemokines that recruit inflammatory cells into the tumour microenvironment, including antigen-presenting cells that activate cytotoxic T-cell function. By contrast, radiation can attract immunosuppressive cells into the tumour microenvironment. In rare circumstances, the antitumour effect of radiotherapy has been observed outside of the radiation field, known as the abscopal effect. This phenomenon is proposed to have an immune origin and indicates that local radiotherapy elicits systemic effects. Herein, we highlight data that provide new mechanistic explanations for the success or failure of radiotherapy, and postulate how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure. We use the concept of radiation- induced tumour equilibrium (RITE) as a starting point to discuss the mechanistic influence of immune-checkpoint therapies on radiotherapy efficacy.

Background: Lichen sclerosus (LS) is a difficult to treat, often relapsing disease with unknown background. Autoimmune diseases also coexist with LS. Over recent years photodynamic therapy (PDT) has been shown to be a noninvasive and successful therapeutic approach for the effective treatment of many conditions. However, the change of immune status of the patients based on ANA antibodies has not been yet reported. Our aim was to observe the clinical response followed by possible changes in autoimmune antibodies levels before and after PDT for LS., Material and Methods: We enrolled 100 women with Lichen sclerosus with or without a concomitant autoimmune disease. All patients received 10 cycles of PDT (65 treated with DIOMED Light, 35 with PhotoDYN Light). We assessed autoimmune antibodies before and after PDT in addition to the clinical response evaluation.Two-year prospective controlled before-and-after study., Results: Following PDT, patients showed a significant attenuation in symptoms' intensity (itching, pruritus, vulvar discomfort). After therapy 41% of patients had partial response, 51% of patients had no symptoms and 8% had persistent or worsened symptoms. The most frequent autoimmune disease were thyroid disorders, followed by vitiligo and arthritis. 57% patients with an additional autoimmune disease before PDT had ANA antibodies. The mean level of ANA in this group diminished significantly after PDT treatment (261.74 IU/ml before vs. 123.20 IU/ml after treatment)., Conclusion: Based on our results, we assume that PDT may influence the immune status of patients with Lichen sclerosus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The antimicrobial photodynamic therapy (aPDT) inactivates the target cell via reactions among the photosensitizer (PS), Laser or Led and O 2 . The aim of this study was to evaluate the tissue reaction and cytokine production promoted by aPDT with curcumin photosensitizer., Methods: Polyethylene tubes containing saline solution (control), 5% sodium hypochlorite (NaOCl) and aPDT with curcumin PS 500mg/L, were implanted into dorsal connective tissue of Wistar rats. After 7, 15, 30, 60 and 90days of implantation, the animals were euthanized and the tubes with surrounding tissues were removed. The specimens were divided in two part, one half was processed, fixed and prepared for histological analysis by staining with hematoxylin and eosin. The other half was collected for IL-1β and IL-6 cytokine production using ELISA assay. The results were statistically analyzed by Kruskal-Wallis test followed by Dunn test (p<0.05) for tissue reaction and ANOVA followed by Bonferroni's correction (p<0.05) for ELISA., Results: All groups showed severe tissue reactions at 7days, whilst a significantly decrease by time was observed. Regarding to cytokine production, aPDT increases the IL-1β levels in all periods of time (p<0.05). However, for IL-6 levels, the highest value was observed with aPDT on the 90th day (p<0.05)., Conclusions: aPDT with curcumin PS 500mg/L demonstrated biocompatibility similar to saline solution and induced the IL-1β and IL-6 cytokines production., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To clarify whether extremely low-level microwaves (MW) alone or in combination with p38 inhibitor affect immune cell responses to inhalation exposure of mice to low-level toluene., Materials and Methods: The cytokine profile, heat shock proteins expression, and the activity of several signal cascades, namely, NF-κB, SAPK/JNK, IRF-3, p38 MAPK, and TLR4 were measured in spleen lymphocytes of mice treated to air-delivered toluene (0.6 mg/m 3 ) or extremely low-level microwaves (8.15-18 GHz, 1μW/cm 2 , 1 Hz swinging frequency) or combined action of these two factors., Results: A single exposure to air-delivered low-level toluene induced activation of NF-κB, SAPK/JNK, IFR-3, p38 MAPK and TLR4 pathways. Furthermore, air toluene induced the expression of Hsp72 and enhanced IL-1, IL-6, and TNF-α in blood plasma, which is indicative of a pro-inflammatory response. Exposure to MW alone also resulted in the enhancement of the plasma cytokine values (e.g. IL-6, TNF-α, and IFN-γ) and activation of the NF-κB, MAPK p38, and especially the TLR4 pathways in splenic lymphocytes. Paradoxically, pre-exposure to MW partially recovered or normalized the lymphocyte parameters in the toluene-exposed mice, while the p38 inhibitor XI additionally increased protective activity of microwaves by down regulating MAPKs (JNK and p38), IKK, as well as expression of TLR4 and Hsp90-α., Conclusions: The results suggest that exposure to low-intensity MW at specific conditions may recover immune parameters in mice undergoing inhalation exposure to low-level toluene via mechanisms involving cellular signaling.