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Our organization, Black in Immuno (@BlackInImmuno), was formed in September 2020 to celebrate, support, and amplify Black voices in immunology when social media campaigns like #BlackInTheIvory illuminated the shared overt and covert issues of systemic racism faced by Black researchers in all facets of science, technology, engineering, art, and mathematics. Black in Immuno was cofounded by a group of Black immunology trainees working at multiple institutions globally: Joël Babdor, E. Evonne Jean, Elaine Kouame, Alexis S. Mobley, Justine C. Noel, and Madina Wane. We devised Black in Immuno Week, held November 22–28, 2020, as a global celebration of Black immunologists. The week was designed to advocate for increased diversity and accessibility in immunology, amplify Black excellence in immunology, and create a community of Black immunologists who can support each other to flourish despite barriers in academia and other job sectors. The week contained live panels and scientific talks, a casual networking mixer, online advocacy and amplification sessions, and a series of wellness events. Our live-streamed programs reached over 300 individuals, and thousands of people kept the conversations going globally using #BlackInImmuno and #BlackInImmunoWeek on social media from five continents. Below, we highlight the events and significant takeaways of the week.

Myocardial infarction is a leading cause of death worldwide1. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality2. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

Supplemental Digital Content is available in the text., Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helper and CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross-priming DC in post–myocardial infarction immunopathology through presentation of self-antigen from necrotic cardiac cells to cytotoxic CD8+ T cells. Methods: We induced type 2 myocardial infarction–like ischemic injury in the heart by treatment with a single high dose of the β-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function. Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a−/− mice deficient in DC cross-priming are protected from persistent immune-mediated myocardial damage and decline of cardiac function, likely because of dampened activation of cytotoxic CD8+ T cells. Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of postischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent postischemic immunopathology and heart failure.

Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a twofold increase in the incidence of sudden cardiac death (SCD) compared with the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodeling in response to chronic inflammation in RA. In particular, it focuses on the roles of nonischemic structural remodeling, altered cardiac ionic currents, and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.

Myocardial infarction (MI) is one of the leading causes of global mortality. Over the last decade, acute MI mortality has significantly decreased; however, fatal heart failure remains a common complication for post-MI survivors.[1][1] Lack of oxygen due to MI causes cardiac tissue necrosis and, as a

Heart failure is the common final pathway of a range of conditions resulting in myocardial damage and a major cause of morbidity and mortality worldwide. Strategies to improve tissue repair and prevent heart failure thus remain an urgent clinical need. Recent studies have documented activation of the adaptive immune system in response to myocardial damage and have implicated anti-heart autoimmunity in the development of heart failure. In an attempt to target anti-heart autoimmune responses as new therapeutic avenue, the number of experimental studies using in vivo models of myocardial damage to study the ensuing immune response has surged.The beta-adrenergic agonist isoproterenol-hydrochloride has been used for its cardiac effects in a variety of different dosing and administration regimes. Most prominently, low doses (100mg/kg) induce cardiomyocyte necrosis and have been used to mimic acute myocardial necrotic lesions as seen in myocardial infarction (MI). However, despite significant resource and animal welfare advantages, concerns about off-target effects and clinical relevance have so far limited uptake in the cardiovascular research community.To assess suitability of the isoproterenol model for the analysis of chronic post-MI immunological readouts, we treated C57BL/6J mice with a single intra-peritoneal bolus injection of 160mg/kg isoproterenol. Our results confirm the presence of necrotic lesions in the myocardium with significant resemblance of the histopathology of Type 2 MI. Kidneys develop mild fibrosis secondary to early cardiac damage, while other organs remain unaffected. Most importantly, we showed that isoproterenol treatment causes myocardial inflammation and fibrosis, activation of T cells in the heart-draining mediastinal lymph nodes, deposition of mature antibodies in the myocardium and the presence of auto-antibodies against the heart in the serum 12 weeks after the initial injury.In summary, this simple and cost-effective experimental model with significant animal welfare benefits induces myocardial damage reminiscent of human Type 2 MI, which is followed by a persistent adaptive immune response against the heart. This makes it a suitable and high-throughput model to study pathological mechanisms of anti-heart autoimmunity as well as to test potential immunomodulatory therapeutic approaches.

In vivo forming hydrogels are of interest for diverse biomedical applications due to their ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled using metal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. TiIV or ZrIV) provide a versatile and robust platform for engineering such materials. However, the in situ formation and in vivo response to this new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. The TiIV–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivo gelation), TiIV–tannic acid materials show substantially improved in vitro drug loading and release profile for the corticosteroid dexamethasone (from 10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug delivery and regenerative medicine.

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms. This article has an associated First Person interview with the first author of the paper.

The changing world of scholarly communication and the emerging new wave of ‘Open Science’ or ‘Open Research’ has brought to light a number of controversial and hotly debated topics. Evidence-based rational debate is regularly drowned out by misinformed or exaggerated rhetoric, which does not benefit the evolving system of scholarly communication. This article aims to provide a baseline evidence framework for ten of the most contested topics, in order to help frame and move forward discussions, practices, and policies. We address issues around preprints and scooping, the practice of copyright transfer, the function of peer review, predatory publishers, and the legitimacy of ‘global’ databases. These arguments and data will be a powerful tool against misinformation across wider academic research, policy and practice, and will inform changes within the rapidly evolving scholarly publishing system., info:eu-repo/semantics/published

The changing world of scholarly communication and the emergence of ‘Open Science’ or ‘Open Research’ has brought to light a number of controversial and hotly-debated topics. Yet, evidence-based rational debate is regularly drowned out by misinformed or exaggerated rhetoric, which does not benefit the evolving system of scholarly communication. The aim of this article is to provide a baseline evidence framework for ten of the most contested topics, in order to help frame and move forward discussions, practices and policies. We address preprints and scooping, the practice of copyright transfer, the function of peer review, and the legitimacy of ‘global’ databases. The presented facts and data will be a powerful tool against misinformation across wider academic research, policy and practice, and may be used to inform changes within the rapidly evolving scholarly publishing system.

Although clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF).Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy.These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.

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The immune system is a crucial player in tissue homeostasis and wound healing. A sophisticated cascade of events triggered upon injury ensures protection from infection and initiates and orchestrates healing. While the neonatal mammal can readily regenerate damaged tissues, adult regenerative capacity is limited to specific tissue types, and in organs such as the heart, adult wound healing results in fibrotic repair and loss of function. Growing evidence suggests that the immune system greatly influences the balance between regeneration and fibrotic repair. The neonate mammalian immune system has impaired pro-inflammatory function, is prone to T-helper type 2 responses and has an immature adaptive immune system skewed towards regulatory T cells. While these characteristics make infants susceptible to infection and prone to allergies, it may also provide an immunological environment permissive of regeneration. In this review we will give a comprehensive overview of the immune cells involved in healing and regeneration of the heart and explore differences between the adult and neonate immune system that may explain differences in regenerative ability. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease and cancer. Improving localised delivery of immunosuppressive drugs to inflamed tissue in a non-invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Here, we report a neutrophil-mediated delivery system able to transport drug-loaded nanocarriers to inflamed tissue by exploiting the inherent ability of neutrophils to migrate to inflammatory tissue. This hybrid system (neutrophils loaded with liposomes ex vivo) efficiently migrated in vitro following an inflammatory chemokine gradient. Furthermore, we studied the triggered release of loaded liposomes and re-uptake by target macrophages. The migratory behaviour of liposome-loaded neutrophils was confirmed in vivo by demonstrating the delivery of drug-loaded liposomes to an inflamed skeletal muscle in mice. A single low-dose injection of the hybrid system locally reduced inflammatory cytokine levels. Biodistribution of liposome loaded neutrophils in a human disease relevant myocardial ischemia reperfusion injury (IRI) mouse model after i.v. injection confirmed the ability of injected neutrophils to carry loaded liposomes to inflammation sites. This strategy shows the potential of nanocarrier-loaded neutrophils as a universal platform to deliver anti-inflammatory drugs to promote tissue regeneration in inflammatory diseases.

BACKGROUNDHemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Cardiac magnetic resonance (CMR) imaging is the current gold standard for non-invasive detection of suspected inflammatory damage to the heart and changes in T1 and T2 relaxation times are commonly used to detect edema associated with immune cell infiltration and fibrosis. These measurements also form the basis of the Lake Louise Criteria, which define a framework for the CMR-based diagnosis of myocarditis. However, they do not take into account the possibility of hemorrhage leading to tissue iron deposition which strongly influences T1 and T2 measurements and may complicate interpretation based on these two parameters only.METHODSSystemic inflammation was induced in CFN mice by application of the TLR-7 agonist Resiquimod. Histopathology was performed on heart sections to assess immune cell infiltration (Hematoxylin & Eosin), fibrosis (PicoSirius Red) and tissue iron deposition (Perl’s Prussian Blue). A multi-parametric cardiac MRI tissue mapping approach measuring T1, T2, and T2* relaxation times was established to non-invasively identify these parameters in this small rodent model.RESULTSResiquimod-treated mice developed severe thrombocytopenia and hemorrhagic myocarditis. We identified patches of cardiac hemorrhage based on the presence of two major MRI phenotypes. Increased T2 with normal T1 and T2* values correlated with infiltration/edema only, while decreased T1, T2, and T2* values identify areas with infiltration/edema in the presence of iron indicating hemorrhagic myocarditis.CONCLUSIONWe show that over-activation of the TLR-7 pathway by Resiquimod treatment of CFN mice induces an early immune response reminiscent of excessive systemic inflammation due to viral infection. This causes internal bleeding which manifests most prominently as severe hemorrhagic myocarditis. We optimized a comprehensive noninvasive in vivo MRI approach based on quantitative measurement of T1, T2 and T2* to demonstrate the presence of diffuse myocardial edema, infiltration and iron deposition without the need of contrast agent administration. We propose that adding quantitative T2* mapping to CMR protocols for detection of myocarditis will improve diagnostic sensitivity and interpretation of disease mechanisms.

The immune system responds to acute tissue damage after myocardial infarction (MI) and orchestrates healing and recovery of the heart. However, excessive inflammation may lead to additional tissue damage and fibrosis and exacerbate subsequent functional impairment, leading to heart failure. The appreciation of the immune system as a crucial factor after MI has led to a surge of clinical trials investigating the potential benefits of immunomodulatory agents previously used in hyper-inflammatory conditions, such as autoimmune disease. While the major goal of routine post-MI pharmacotherapy is to support heart function by ensuring appropriate blood pressure and cardiac output to meet the demands of the body, several drug classes also affect a range of immunological pathways and modulate the post-MI immune response, which is crucial to take into account when designing future immunomodulatory trials. This review outlines how routine post-MI pharmacotherapy affects the immune response and may thus influence post-MI outcomes and development towards heart failure. Current key drug classes are discussed, including platelet inhibitors, statins, β-blockers, and renin⁻angiotensin⁻aldosterone inhibitors.

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.

Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function.

The regenerative capacity of adult human tissues and organs is limited, but recent developments have seen the advent of promising new technologies for regenerative therapy. The human heart is of particular interest for regenerative medicine, as cardiac tissue damage is repaired by the formation of rigid scar tissue, which causes inevitable structural changes and progressive functional decline leading to heart failure. Cardiac regenerative medicine aims to prevent scar formation or replace existing scars to halt or reverse adverse remodeling and therapeutic approaches include the use of biomaterials, gene therapies, delivery of growth factors, and (stem) cell therapies. Regenerative therapies, however, face significant obstacles in a hostile microenvironment. While the early immune response to a myocardial infarct is essential to ensure tissue integrity and to avoid fatal cardiac rupture, excessive activation of endogenous repair mechanisms may lead to ongoing inflammation, fibrosis, and sustained autoimmune-mediated tissue damage. Anti-cardiac autoreactivity of the adaptive immune system has been suggested to be involved in structural remodeling, functional decline, and the development of heart failure. It is, therefore, crucial to first understand the endogenous response to cardiac tissue damage and how to restore immune tolerance to cardiac tissue, before additional regenerative therapies can achieve their full potential.

The immune system was identified as a protective factor during infectious diseases over a century ago. Current definitions and textbook information are still largely influenced by these early observations, and the immune system is commonly presented as a defence machinery. However, host defence is only one manifestation of the immune system's overall function in the maintenance of tissue homeostasis and system integrity. In fact, the immune system is integral part of fundamental physiological processes such as development, reproduction and wound healing, and a close crosstalk between the immune system and other body systems such as metabolism, the central nervous system and the cardiovascular system is evident. Research and medical professionals in an expanding range of areas start to recognise the implications of the immune system in their respective fields.This chapter provides a brief historical perspective on how our understanding of the immune system has evolved from a defence system to an overarching surveillance machinery to maintain tissue integrity. Current perspectives on the non-defence functions of classical immune cells and factors will also be discussed.

Biomaterial interfaces can present soluble and physical cues on the nano- and micro-scale to control T cell behaviour., Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function.

The immune system was identified as a protective factor during infectious diseases over a century ago. Current definitions and textbook information are still largely influenced by these early observations, and the immune system is commonly presented as a defence machinery. However, host defence is only one manifestation of the immune system’s overall function in the maintenance of tissue homeostasis and system integrity. In fact, the immune system is integral part of fundamental physiological processes such as development, reproduction and wound healing, and a close crosstalk between the immune system and other body systems such as metabolism, the central nervous system and the cardiovascular system is evident. Research and medical professionals in an expanding range of areas start to recognise the implications of the immune system in their respective fields. This chapter provides a brief historical perspective on how our understanding of the immune system has evolved from a defence system to an overarching surveillance machinery to maintain tissue integrity. Current perspectives on the non-defence functions of classical immune cells and factors will also be discussed

Allergic contact dermatitis (ACD) is triggered by an aberrant hyperinflammatory immune response to innocuous chemical compounds and ranks as the world’s most prevalent occupational skin condition. Although a variety of immune effector cells are activated during ACD, regulatory T (Treg) cells are crucial in controlling the resulting inflammation. Insulin-like growth factor-1 (IGF-1) regulates cell proliferation and differentiation and accelerates wound healing and regeneration in several organs including the skin. Recently IGF-1 has also been implicated in protection from autoimmune inflammation by expansion of Treg cells. Here, we demonstrate that ectopic expression of IGF-1 in mouse skin suppresses ACD in a Treg cell-specific manner, increasing the number of Foxp3+ Treg cells in the affected area and stimulating lymphocyte production of the anti-inflammatory cytokine interleukin 10. Similar therapeutic effects can be achieved with systemic or topical delivery of IGF-1, implicating this growth factor as a promising new therapeutic option for the treatment of ACD.

Regulatory B cells (Breg) have attracted increasing attention for their roles in maintaining peripheral tolerance. Interleukin 33 (IL-33) is a recently identified IL-1 family member, which leads a double-life with both pro- and anti-inflammatory properties. We report here that peritoneal injection of IL-33 exacerbated inflammatory bowel disease in IL-10-deficient (IL-10−/−) mice, whereas IL-33-treated IL-10-sufficient (wild type) mice were protected from the disease induction. A phenotypically unconventional subset(s) (CD19+CD25+CD1dhiIgMhiCD5-CD23-Tim-1-) of IL-10 producing Breg-like cells (BregIL-33) was identified responsible for the protection. We demonstrated further that BregIL-33 isolated from these mice could suppress immune effector cell expansion and functions and, upon adoptive transfer, effectively blocked the development of spontaneous colitis in IL-10−/− mice. Our findings indicate an essential protective role, hence therapeutic potential, of BregIL-33 against mucosal inflammatory disorders in the gut., Highlights • IL-33, a branded ‘Th2’ cytokine, could accelerate the Th1-mediated colitis under an IL-10 deficient condition. • IL-10 sufficient mice were protected from the IL-33-mediated mucosal inflammation. • IL-33 induced a phenotypically unique subset of IL-10-producing regulatory B cells (BregIL-33). • Adoptive transfer of BregIL-33 blocked the spontaneous colitis in IL-10-deficient mice (therapeutic potential). • Our findings offer new insights into the immunological mechanisms underlying mucosal inflammation, and its regulation.

The orphan receptor CLEC-1 is part of a subfamily of C-type lectin-like receptors, which is encoded in the human natural killer gene complex and comprises several pattern recognition receptors important for innate immune functions. As information on human CLEC-1 is still very limited, we aimed to further characterize this receptor. Similar to another subfamily member, LOX-1, expression of CLEC-1 mRNA was detected in myeloid cells as well as in endothelial cells. CLEC-1 protein displayed N-linked glycosylation and formed dimers. However, in contrast to other members of the subfamily, expression levels were upregulated by transforming growth factor (TGF)-β, but not significantly affected by proinflammatory stimuli. It is intriguing that human CLEC-1 could only be detected intracellularly with a staining pattern resembling endoplasmic reticulum proteins. Neither TGF-β nor inflammatory stimuli could promote significant translocation to the cell surface. These findings are in accordance with a primarily intracellular localization and function of human CLEC-1.

The myeloid cluster within the natural killer (NK) gene complex comprises several C-type lectin-like receptor genes of diverse and highly important functions in the immune system such as LOX-1 and DECTIN-1. Based on sequences that have become available by whole genome sequencing, we conducted a comparison of the human, chimpanzee, mouse and rat NK gene complex to better characterize this gene family and additional genes of this region in regard of their phylogenetic relationship and evolution within the complex. We found that the arrangement of genes within the primate cluster differs from the order and orientation of the corresponding genes in the rodent complex which can be explained by evolutionary duplication and inversion events. Analysis of individual genes revealed a high sequence conservation supporting the prime importance of the encoded proteins. Expression analyses of the more recently described CLEC12B and CLEC9A genes displayed not only mRNA expression in monocytic and dendritic cells, but in contrast to other members of the family also in lymphocytes. Further, two additional genes were identified, which do not encode proteins with lectin-like domain structure and seem to be widely expressed.

XIAP (X chromosome-linked inhibitor of apoptosis) is a member of the anti-apoptotic IAP gene family and an inhibitor of caspase-3. We show here that loss of XIAP renders cells highly sensitive to oxidative stress. Stimulation of XIAP−/− MEF with hydrogen peroxide, or other agents that generate reactive oxygen species (ROS) results in increased apoptosis assessed by caspase-3 activity and PARP cleavage. Furthermore, we observed increased levels of ROS and diminished expression of antioxidative genes, e.g., SOD1, -2, NQO1, HO-1, and Txn2 in XIAP−/− cells. In addition, stimulation of XIAP−/− MEF with hydrogen peroxide resulted in enhanced phosphorylation of JNK. Our findings reveal that XIAP, in addition to its well described caspase-inhibitory function, prevents prolonged JNK activation and is critically involved in modulating ROS levels through regulation of antioxidative genes, thereby inhibiting ROS-induced apoptosis.

In spite of considerable interest in the field, reprogramming induced pluripotent stem cells (iPSCs) directly from cancer cells has encountered considerable challenges, including the extremely low reprogramming efficiency and instability of cancer-derived iPSCs (C-iPSCs). In this study, we aimed to identify the main obstacles that limit cancer cell reprogramming. Through a detailed multidimensional kinetic optimization, a highly optimized protocol is established for reprogramming C-iPSCs using nonviral plasmid vectors. We demonstrated how the initial cancer cell density seeded could be the most critical factor ultimately affecting C-iPSCs reprogramming. We have consistently achieved an unprecedented high C-iPSC reprogramming efficiency, establishing stable colonies with typical iPSC morphology, up to 50% of which express the iPSC phenotypic (Oct3/4, Sox2, Nanog) and enzymatic (alkaline phosphatase) markers. Furthermore, established C-iPSC lines were shown to be capable of forming teratomas in vivo, containing cell types and tissues from each of the embryonic germ layers, fully consistent with their acquisition of pluripotency. This protocol was tested and confirmed in two completely unrelated human lung adenocarcinoma (A549) and mouse melanoma (B16f10) cancer cell lines and thus offers a potentially valuable method for generating effectively virus-free C-iPSCs for future applications.

Interleukin (IL)-33 is a recently identified pleiotropic cytokine, which can orchestrate complex innate and adaptive immune responses in immunity and disease. It has been characterized as a cytokine of the IL-1 family and affects a wide range of immune cells by signalling through its receptor ST2L. Accumulating evidence suggests a crucial role of IL-33/ST2 in inducing and modifying host immune responses against a variety of pathogens including parasites, bacteria, viruses and fungi as well as sterile insults of both endogenous and exogenous source. In this review, we endeavour to give a comprehensive overview of the current knowledge about the role of IL-33 and its receptor ST2 in host defence against infections.