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Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.

Iron is an essential micronutrient and a critical cofactor for proteins involved in fundamental processes such as oxygen transport, energy production and DNA synthesis. However, iron levels need to be tightly balanced to avoid pathological consequences of iron overload or deficiency. Genetically engineered mouse models with alterations in systemic or cellular iron handling advanced our knowledge how systemic and cellular iron homeostasis is maintained. Here, we prepared a comprehensive overview of mouse models that provide insight into mechanisms of iron regulation and/or rare or frequent iron-related disorders.

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6C(lo) macrophages toward increased numbers of inflammatory Ly6C(hi) monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6C(hi) monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.

Background We aimed at clarifying the role of lipocalin-2 (LCN-2) in clear-cell renal cell carcinoma (ccRCC). Since LCN-2 was recently identified as a novel iron transporter, we explored its iron load as a decisive factor in conferring its biological function. Methods LCN-2 expression was analysed at the mRNA and protein level by using immunohistochemistry, RNAscope® and qRT-PCR in patients diagnosed with clear-cell renal cell carcinoma compared with adjacent healthy tissue. We measured LCN-2-bound iron by atomic absorption spectrometry from patient-derived samples and applied functional assays by using ccRCC cell lines, primary cells, and 3D tumour spheroids to verify the role of the LCN-2 iron load in tumour progression. Results LCN-2 was associated with poor patient survival and LCN-2 mRNA clustered in high- and low-expressing ccRCC patients. LCN-2 protein was found overexpressed in tumour compared with adjacent healthy tissue, whereby LCN-2 was iron loaded. In vitro, the iron load determines the biological function of LCN-2. Iron-loaded LCN-2 showed pro-tumour functions, whereas iron-free LCN-2 produced adverse effects. Conclusions We provide new insights into the pro-tumour function of LCN-2. LCN-2 donates iron to cells to promote migration and matrix adhesion. Since the iron load of LCN-2 determines its pro-tumour characteristics, targeting either its iron load or its receptor interaction might represent new therapeutic options.

Introduction: Survival in gastric cancer is often limited by peritoneal carcinomatosis, which supposedly develops from serosal tumor infiltration or tumor cell spread during gastrectomy with lymphadenectomy. To eliminate peritoneal tumor cells, extensive intraperitoneal lavage (EIPL) has been suggested. Impressive results have been achieved in Japanese trials. In this trial, we assessed EIPL in Western patients. Methods: This prospective trial included patients with non-metastatic gastric adenocarcinoma undergoing gastrectomy with D2 lymphadenectomy. Peritoneal fluid samples at laparotomy, after lymphadenectomy, and after EIPL were analyzed for tumor cells using cytology and EpCAM antibodies. The primary endpoint was peritoneal conversion rate (PCR; proportion of patients in whom EIPL eliminated tumor cells after lymphadenectomy). Secondary endpoints were peritoneal release rate (PRR; proportion of patients with peritoneal tumor cells after gastrectomy/lymphadenectomy among all patients without cells before gastrectomy/lymphadenectomy) and prevalence of peritoneal tumor cells before resection. EIPL was considered ineffective if PCR ⩽ 0.2 and warranted further exploration if PCR ⩾ 0.5. Clinicaltrials.gov identifier is NCT01476553. Results: The trial was stopped early because tumor cells after gastrectomy/lymphadenectomy were detected in only 3/27 (11.1%) patients. In none of these did EIPL eliminate tumor cells (PCR 0, 95% confidence interval [CI] 0%–12.5%). In 8/27 (29.6%) patients, tumor cells were detected after EIPL. PRR was 11.1% (95% CI 2.4%–29.2%). There were no perioperative complications higher than Clavien-Dindo grade 3a. Conclusions: In Western patients, free peritoneal tumor cells after gastrectomy with D2 lymphadenectomy for gastric cancer were detected only sporadically. Although based on few cases, the findings suggest that EIPL spreads tumor cells into the peritoneal cavity, thus being potentially harmful. Therefore, EIPL cannot be generally recommended.

Purpose Optimal perfusion of the gastric conduit during esophagectomy is elementary for the anastomotic healing since poor perfusion has been associated with increased morbidity due to anastomotic leaks. Until recently surgical experience was the main tool to assess the perfusion of the anastomosis. We hypothesized that anastomoses located in the zone of optimal ICG perfusion of the gastric conduit ("optizone") have a reduced anastomotic leakage rate after esophagectomy. Methods Indocyanine green (ICG) fluorescence tissue angiography was used to evaluate the anastomotic perfusion in 35 patients undergoing esophagectomy with gastric conduit reconstruction. The transition point of the "optizone" to the malperfused area of the conduit was defined macroscopically and with the use of ICG angiography during the operation. The anastomosis was performed in the optizone whenever possible. The results of the ICG patients were retrospectively reviewed and compared with 55 patients previously operated without ICG angiography. Results The visual assessment of the conduit perfusion concurred with the ICG angiography in 27 cases. In 8 cases (22.8%) the ICG angiography deviated from the visual aspect. One case of anastomotic leakage was observed in the group of patients in which the anastomosis could be performed in the optizone (1/33; 3%) compared with 10 cases in the control group (18%; p = 0.04). In two cases we had to perform the anastomosis in an area of compromised ICG perfusion. Both patients developed an anastomotic leakage. Conclusions ICG tissue angiography represents a feasible and reliable technical support in the evaluation of the anastomotic perfusion after esophagectomy. In this retrospective analysis we observed a significant decrease in anastomotic leakage rate when the anastomosis could be placed in the zone of good perfusion defined by ICG fluorescence. A prospective trial is needed in order to provide higher level evidence for the use of ICG fluorescence in reducing leakage rates after esophagectomy.

Iron is an essential element for virtually all organisms. It facilitates cell proliferation and growth but also contributes to major hallmarks of cancer such as tumor initiation, growth, and metastasis. Often, iron handling of tumor cells is disturbed, with altered iron acquisition, efflux, and storage. Targeting perturbed iron metabolic pathways might open opportunities towards novel approaches in cancer treatment. It is becoming clear that cells of the tumor microenvironment such as macrophages contribute to tumor progression. Since macrophages evolved a multitude of mechanisms to sequester, transport, store, and release iron it can be speculated that tumor cells educate them to supply iron to support tumor growth. Recent evidence supports the existence of transferrin-independent iron transport mechanisms in the tumor microenvironment, which points to local iron transport proteins such as lipocalin-2 and/or low molecular weight iron-trafficking substances such as siderophores. We hypothesize that tumor cells educate immune cells, i.e. macrophages in their neighborhood to make them delivering iron for the benefit of cancer progression. In particular, we pay attention to recent developments, pointing to lipocalin-2 and siderophores as alternative iron transport molecules in the tumor microenvironment.

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.

Many randomized controlled trials in which motivational interviewing (MI) is a key intervention make no provision for the assessment of treatment fidelity. This methodological shortcoming makes it impossible to distinguish between high- and low-quality MI interventions, and, consequently, to know whether MI provision has contributed to any intervention effects. This article makes some practical recommendations for the collection, selection, coding and reporting of MI fidelity data, as measured using the Motivational Interviewing Treatment Integrity Code. We hope that researchers will consider these recommendations and include MI fidelity measures in future studies.

A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.

Tumor cell-derived factors skew macrophages toward a tumor-supporting phenotype associated with the secretion of protumorigenic mediators. Apoptosing tumor cells release sphingosine 1-phosphate (S1P), which stimulates the production of lipocalin 2 (LCN2) in tumor-associated macrophages and is associated with tumor metastasis. We explored the mechanism by which S1P induces LCN2 in macrophages and investigated how this contributed to tumor growth and metastasis. Knockdown of S1P receptor 1 (S1PR1) in primary human macrophages and experiments with bone marrow-derived macrophages from S1PR1-deficient mice showed that S1P signaled through S1PR1 to induce LCN2 expression. The LCN2 promoter contains a consensus sequence for signal transducer and activator of transcription 3 (STAT3), and deletion of the STAT3 recognition sequence reduced expression of an LCN2-controlled reporter gene. Conditioned medium from coculture experiments indicated that the release of LCN2 from macrophages induced tube formation and proliferation in cultures of primary human lymphatic endothelial cells in a manner dependent on the kinase PI3K and subsequent induction of the growth factor VEGFC, which functioned as an autocrine signal stimulating the receptor VEGFR3. Knockout of Lcn2 attenuated tumor-associated lymphangiogenesis and breast tumor metastasis both in the breast cancer model MMTV-PyMT mice and in mice bearing orthotopic wild-type tumors. Our findings indicate that macrophages respond to dying tumor cells by producing signals that promote lymphangiogenesis, which enables metastasis.

BACKGROUND: Content validity, the proper reflection of the concept to be measured, is yet unknown for the Credibility and Expectancy Questionnaire (CEQ). It is frequently used in pain rehabilitation because treatment expectancy is influential on the outcome.OBJECTIVE: To test and improve the content validity of the CEQ in a sample of patients with chronic pain in different phases of their treatment.METHODS: A qualitative observational study design using the Three-Step Test-Interview method was used. Therein, data collection, analyses, and adaptations occur iteratively.RESULTS: Seventeen patients with chronic pain in different stages of treatment participated through convenience sampling from the mother sample of a randomized controlled trial. The main study parameter is content validity, which is defined as (1) interpretations and responses of the participants and (2) the identification of response problems operationalized, and resulting in changes in the CEQ. For patients waiting for treatment, the written instruction of the CEQ allowed different interpretations. After changing the instructions, the CEQ became an easy-to-understand and content-valid questionnaire. For patients who had already undergone treatment, changes regarding time frame and recall period were necessary to overcome interpretation and response problems to the CEQ.DISCUSSION: After small changes, the CEQ appeared to be a content-valid measurement instrument for patients waiting for treatment. However, for patients who had already undergone treatment, the content validity of the CEQ was less, and considerable changes were necessary.

Background: Chronically ill patients need to adapt to their impaired life condition. Social (e.g. social support), material (e.g. income) and personal (e.g. mastery) resources are needed to cope with this challenge. It is, however, less clear whether these factors also contribute to 'relatively successful functioning' and whether these effects are disease specific or generic across chronic diseases. Methods: Baseline data from 361 Dutch men and women aged epsilon 60 years who were mildly depressed and diagnosed with type 2 diabetes or chronic obstructive pulmonary disease (COPD) were used. These persons participated in the 'Depression in Elderly with Long-Term Afflictions' (DELTA) study. Logistic regression analyses were used to study the independent association of social support, income and mastery (independent variables) with physical, mental and social functioning (dependent variables). Results: A high level of mastery is significantly associated with physical, mental and social functioning in the total study population, as well as in subgroups of patients with COPD or diabetes. This relationship remained significant after controlling for confounding factors such as gender, age, educational level and the other remaining resources. In diabetes patients, high levels of social support and income also contributed significantly to successful social functioning. Conclusion: Our findings suggest that rather than having good friends and a high income, having a high level of mastery (resilience) might best help chronically ill patients in coping with and adapting to their often co-morbid condition. Further longitudinal research is necessary to unravel the long-term effects of mastery, income and social support on 'relatively successful functioning' in chronically ill patients.

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Cytosolic DNA that emerges during infection with a retrovirus or DNA virus triggers antiviral type I interferon responses. So far, only double-stranded DNA (dsDNA) over 40 base pairs (bp) in length has been considered immunostimulatory. Here we found that unpaired DNA nucleotides flanking short base-paired DNA stretches, as in stem-loop structures of single-stranded DNA (ssDNA) derived from human immunodeficiency virus type 1 (HIV-1), activated the type I interferon-inducing DNA sensor cGAS in a sequence-dependent manner. DNA structures containing unpaired guanosines flanking short (12- to 20-bp) dsDNA (Y-form DNA) were highly stimulatory and specifically enhanced the enzymatic activity of cGAS. Furthermore, we found that primary HIV-1 reverse transcripts represented the predominant viral cytosolic DNA species during early infection of macrophages and that these ssDNAs were highly immunostimulatory. Collectively, our study identifies unpaired guanosines in Y-form DNA as a highly active, minimal cGAS recognition motif that enables detection of HIV-1 ssDNA.

Macrophages are central in regulating iron homeostasis, which is tightly linked to their versatile role during innate immunity. They sequester iron by phagocytosis of senescent erythrocytes and represent a major source of available iron in the body. Macrophage iron homeostasis is coupled to the functional heterogeneity and plasticity of these cells, with their extreme roles during inflammation, immune modulation, and resolution of inflammation. It is now appreciated that the macrophage polarization process dictates expression profiles of genes involved in iron metabolism. Therefore, macrophages have evolved a multitude of mechanisms to sequester, transport, store, and release iron. A new, enigmatic protein entering the iron scene and affecting the macrophage phenotype is lipocalin-2. Iron sequestration in macrophages depletes the microenvironment, thereby limiting extracellular pathogen or tumor growth, while fostering inflammation. In contrast, iron release from macrophages contributes to bystander cell proliferation, which is important for tissue regeneration and repair. This dichotomy is also reflected by the dual role of lipocalin-2 in macrophages. Unfortunately, the iron release macrophage phenotype is also a characteristic of tumor-associated macrophages and stimulates tumor cell survival and growth. Iron sequestration versus its release is now appreciated to be associated with the macrophage polarization program and can be used to explain a number of biological functions attributed to distinct macrophage phenotypes. Here we discuss macrophage iron homeostasis with a special focus on lipocalin-2 related to the formation and function of tumor-associated macrophages.

Contains fulltext : 125398.pdf (Publisher’s version ) (Open Access) BACKGROUND: Non-adherence and drop-out are major problems in pain rehabilitation. For patients with various health problems, motivational interviewing (MI) has shown promising effects to tackle these problems. In chronic pain patients, the effectiveness of MI is however unknown. Therefore, a MI-based pre-pain rehabilitation intervention (MIP) addressing motivation, expectations, and beliefs has been developed to prepare eligible patients for rehabilitation treatment. METHODS/DESIGN: Study design: A parallel randomized controlled trial including two interventions: a motivational interviewing pre-pain rehabilitation intervention (MIP) and a usual care (UC) control arm. Follow-up will be 6 months after completion of rehabilitation treatment.Study population: One hundred and sixty (n = 80 per arm) patients with chronic non-specific musculoskeletal pain visiting an outpatient rehabilitation department, who are eligible to participate in an outpatient cognitive behavioral pain rehabilitation program.Intervention: MIP consists of two sessions to prepare and motivate the patient for pain rehabilitation treatment and its bio psychosocial approach. UC consists of information and education about the etiology and the general rehabilitation approach of chronic pain. Both the MIP and UC contain two sessions of 45 to 60 minutes each.Objective: The aim of the current study is to evaluate the effectiveness of MIP compared to UC in terms of an increase in the long-term level of societal participation and decrease of drop-out during rehabilitation treatment.Main study endpoints: Primary outcome is the change in level of participation (according to the ICF-definition: 'involvement in a life situation') 6 months after completion of rehabilitation treatment. Secondary outcomes are adherence and treatment drop-out, disability, pain intensity, self-reported main complaints, (pain-specific) self-efficacy, motivation, and quality of life. Costs are calculated including the costs of the pre-treatment intervention, productivity losses, and healthcare utilization. Potential moderators and active ingredients of MI are explored. For the process evaluation, parameters such as MI fidelity, feasibility, and experiences are explored. DISCUSSION: The results of this study will provide evidence on the effectiveness of this MI-based pre-treatment in pain rehabilitation. Furthermore, a cost-effectiveness analysis and exploration of moderating and working mechanisms of MI and an extensive process evaluation takes place. TRIAL REGISTRATION: Nederlands trial register NTR3065.

Background Chronically ill patients often experience psychosocial problems in everyday life. A biopsychosocial approach is considered to be essential in chronic care. In Dutch primary health care the current biomedically oriented clinical practice may conflict with the biopsychosocial approach. This study is aimed to explore the views of Dutch stakeholders on achieving a biopsychosocial approach to the care of patients with chronic diseases. Methods In a qualitative explorative study design, we held semi-structured interviews with stakeholders, face-to-face or by telephone. Data were analysed using content analysis. Thirty representatives of Dutch patients with chronic illnesses, primary care professionals, policy makers, health inspectorate, health insurers, educational institutes and researchers were interviewed. Results Stakeholders were aware that a systematic biopsychosocial care approach is lacking in current practice. Opportunities for effective change are multidimensional. Achieving a biopsychosocial approach to care relates to active patient participation, the training of professionals, high-quality guidelines, protocols and tools, integrated primary care, research and financial issues. Conclusions Although the principles and importance of the biopsychosocial model have been recognized, the provision of care that starts from the medical, emotional or social needs of individual patients does not fit in easily with the current Dutch health care system. All parties involved need to make a commitment to realize the ideal of biopsychosocial chronic care. Together they need to equip health professionals with skills to understand patients' multifaceted needs and to reward integrated biopsychosocial care. Patients need to be empowered to be active partners in their own care.

Macrophages are dynamic cells integrating signals from their microenvironment to develop specific functional responses. Although, microarray-based transcriptional profiling has established transcriptional reprogramming as an important mechanism for signal integration and cell function of macrophages, current knowledge on transcriptional regulation of human macrophages is far from complete. To discover novel marker genes, an area of great need particularly in human macrophage biology but also to generate a much more thorough transcriptome of human M1- and M1-like macrophages, we performed RNA sequencing (RNA-seq) of human macrophages. Using this approach we can now provide a high-resolution transcriptome profile of human macrophages under classical (M1-like) and alternative (M2-like) polarization conditions and demonstrate a dynamic range exceeding observations obtained by previous technologies, resulting in a more comprehensive understanding of the transcriptome of human macrophages. Using this approach, we identify important gene clusters so far not appreciated by standard microarray techniques. In addition, we were able to detect differential promoter usage, alternative transcription start sites, and different coding sequences for 57 gene loci in human macrophages. Moreover, this approach led to the identification of novel M1-associated (CD120b, TLR2, SLAMF7) as well as M2-associated (CD1a, CD1b, CD93, CD226) cell surface markers. Taken together, these data support that high-resolution transcriptome profiling of human macrophages by RNA-seq leads to a better understanding of macrophage function and will form the basis for a better characterization of macrophages in human health and disease.

Summary Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3′ repair exonuclease 1 (TREX1)-mediated degradation. Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN). Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity.