Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous ...negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.
Horizon scanning is intended to identify the opportunities and threats associated with technological, regulatory and social change. In 2017 some of the present authors conducted a horizon scan for ...bioengineering (Wintle et al., 2017). Here we report the results of a new horizon scan that is based on inputs from a larger and more international group of 38 participants. The final list of 20 issues includes topics spanning from the political (the regulation of genomic data, increased philanthropic funding and malicious uses of neurochemicals) to the environmental (crops for changing climates and agricultural gene drives). The early identification of such issues is relevant to researchers, policy-makers and the wider public.
Abstract
Objective
Delivery of the stromal cell-derived cytokine IL-33 protects allografts from rejection by acting on CD11c+ DC that facilitate the expansion of regulatory T cells (Treg). IL-33 ...administration also permits tolerance induction at doses of co-stimulatory blockade that fails on their own. Based on these data we hypothesized that IL-33-stimulated DC represent a tolerogenic DC subset and their precise examination will define biochemical pathways that contribute to tolerogenic DC functions.
Methods
Mouse bone marrow-derived CD11c+ DCs were treated with lipopolysaccharide (LPS) or IL-33 before nitric oxide (NO) generation, glucose and fatty acid uptake, and mitochondrial function and potential were assessed by EPR spectroscopy, flow cytometry, and Seahorse analysis.
Results
DC responded to the TLR4 ligand LPS by generating high levels of NO and shifting their metabolic activity to aerobic glycolysis. This was in stark contrast to IL-33, which caused a metabolic reprogramming in DC that involved augmented mitochondrial basal respiration, ATP production, and maximum respiration. IL-33-stimulated DC also displayed increase mitochondrial potential and a profound increase in the uptake of fatty acids.
Conclusions
It has emerged that immunogenic DCs undergo metabolic changes that enables their pro-inflammatory functions. The metabolic underpinnings of tolerogenic DCs is less understood. Here we show that IL-33-stimulated DC, which potently expand Treg, rely on oxidative phosphorylation and uptake fatty acids. These data suggest IL-33 initiates metabolic reprogramming matching those found in regulatory myeloid populations, including tumor associated DC and alternatively activated macrophages.
The war for the future Forsythe, Samuel; Rößing, Anna
New perspectives (Prague, Czech Republic),
09/2020, Letnik:
28, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The following essay was born out of the authors’ participation in the Hamburg (Insecurity) Sessions 2019: Un-Cancelling the Future, and the discussions that took place in the workshop on Future ...Weapons and Emerging Technologies. The workshop participants critically addressed such problems as the future of defence technologies and their sociotechnical environments, cybersecurity and surveillance proliferation and the improvised instruments of insurgency. Our task was to weave the ideas and insights of the workshop’s participants into a vision of the world in 2040 and use it to motivate an analysis of the technoscientific imaginaries emerging in the present. From the workshop presentations and discussions, we identified three key areas of that allowed us to imagine the outlines and interactions of global security and technoscientific practice in 2040: ecopolitics: the exploitation of ecological systems for strategic ends; technonationalism: the use of advanced technologies to pursue racialised and nationalistic geopolitical agendas; and the security continuum: the extension of conflict modes to all aspects of social life and the open-source proliferation of security tools and techniques.
Abstract
BACKGROUND
FoxP3+ regulatory T cells (Tregs) are crucial to self- and antigen-specific tolerance. IL-33 drives expansion of Tregs expressing the IL-33 receptor, ST2, and secreting high ...levels of IL-10. Regulatory B cells (Bregs) are recently identified negative regulators of the immune system and depend on IL-10 to suppress effector T cell responses. In new data, we find that IL-33 also expands Bregs, however, the relationship between ST2+ Treg and Bregs cells remains unknown. Herein we elucidated if a directional relationship exists between IL-33-expanded Bregs and Tregs.
METHODS
B6 eGFP-FoxP3-Diptheria Toxin (DT) receptor mice were used to establish whether IL-33-expanded Treg were needed for IL-33-aided increases of TIM-1+ IL-10+ Bregs. B6 Foxp3-Cre X IL-10fl/fl mice were used to determine the need for IL-10 expression by Tregs for IL-33-mediated expansion of Bregs.
RESULTS
Assessment of splenocytes for Tregs and Bregs by flow cytometry showed that IL-33 administration led to a 3–5-fold increase in ST2+ Tregs. IL-33 also led to a 3-fold increase in the frequency of IL-10+ Breg, most of which expressed ST2. A lack of Tregs hindered the ability of IL-33 to increase Bregs. While Treg expression IL-10 was not required for ST2+ Treg expansion by IL-33, IL-10 expression by Tregs is crucial for Breg expansion by IL-33.
CONCLUSIONS
We have uncovered a relationship between Tregs and Bregs in response to IL-33. Specifically, while we show that Bregs express ST2, our data suggest that IL-33 expansion of Bregs is indirectly mediated by Treg IL-10 production.
Biosecurity Revill, James; Roessing, Anna
The Oxford Handbook of the International Law of Global Security,
02/2021
Book Chapter
This chapter discusses the term ‘biosecurity’, which is a relatively new addition to the global security lexicon. It looks at the origins and evolution of the concept of biosecurity, drawing ...attention to drivers of interest in biosecurity and the linguistic, cultural, and political challenges to cohesively defining this concept. Notwithstanding such conceptual difficulties, biosecurity has become an important topic in twenty-first-century security discourse as multilateral and national security-policymaking organs have recognized the potential security-related risks associated with contemporary biotechnology and have sought to mitigate such risks. The chapter then elaborates on what has been achieved in terms of building a biosecurity architecture. It also considers the current status of the biosecurity debate, drawing on examples from the patchwork of biosecurity measures undertaken across the globe to illustrate how this is an area that has made considerable progress over the course of the last two decades. Ultimately, biosecurity is a work in progress that will become increasingly salient in the global security discourse as life sciences and biotechnology continue to advance in a changing geostrategic context.
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