The endocannabinoid anandamide activates pro-resolving pathways in human primary macrophages by engaging both CB2 and GPR18 receptors.

Resolution of inflammation is the cellular and molecular process that protects from widespread and uncontrolled inflammation and restores tissue function in the aftermath of acute immune events. This process is orchestrated by specialized pro-resolving mediators (SPM), a class of bioactive lipids able to reduce immune activation and promote removal of tissue debris and apoptotic cells by macrophages. Although SPMs are the lipid class that has been best studied for its role in facilitating the resolution of self-limited inflammation, a number of other lipid signals, including endocannabinoids, also exert protective immunomodulatory effects on immune cells, including macrophages. These observations suggest that endocannabinoids may also display pro-resolving actions. Interestingly, the endocannabinoid anandamide (AEA) is not only known to bind canonical type 1 and type 2 cannabinoid receptors (CB1 and CB2) but also to engage SPM-binding receptors such as GPR18. This suggests that AEA may also contribute to the governing of resolution processes. In order to interrogate this hypothesis, we investigated the ability of AEA to induce pro-resolving responses by classically-activated primary human monocyte-derived macrophages (MoDM). We found that AEA, at nanomolar concentration, enhances efferocytosis in MoDMs in a CB2- and GPR18-dependent manner. Using lipid mediator profiling, we also observed that AEA modulates SPM profiles in these cells, including levels of resolvin (Rv)D1, RvD6, maresin (MaR)2, and RvE1 in a CB2-dependent manner. AEA treatment also modulated the gene expression of SPM enzymes involved in both the formation and further metabolism of SPM such as 5-lipoxygenase and 15-Prostaglandin dehydrogenase. Our findings show, for the first time, a direct effect of AEA on the regulation of pro-resolving pathways in human macrophages. They also provide new insights into the complex interactions between different lipid pathways in activation of pro-resolving responses contributing to the reestablishment of homeostasis in the aftermath of acute inflammation.

Cellular and Molecular Effects of Microgravity on the Immune System: A Focus on Bioactive Lipids.

Microgravity is one of the main stressors that astronauts are exposed to during space missions. This condition has been linked to many disorders, including those that feature dysfunctional immune homeostasis and inflammatory damage. Over the past 30 years, a significant body of work has been gathered connecting weightlessness-either authentic or simulated-to an inefficient reaction to pathogens, dysfunctional production of cytokines and impaired survival of immune cells. These processes are also orchestrated by a plethora of bioactive lipids, produced by virtually all cells involved in immune events, which control the induction, magnitude, outcome, compartmentalization and trafficking of immunocytes during the response to injury. Despite their crucial importance in inflammation and its modulation, however, data concerning the role of bioactive lipids in microgravity-induced immune dysfunctions are surprisingly scarce, both in quantity and in variety, and the vast majority of it focuses on two lipid classes, namely eicosanoids and endocannabinoids. The present review aims to outline the accumulated knowledge addressing the effects elicited by microgravity-both simulated and authentic-on the metabolism and signaling of these two prominent lipid groups in the context of immune and inflammatory homeostasis.

Simulated Microgravity Affects Pro-Resolving Properties of Primary Human Monocytes.

Space-related stressors such as microgravity are associated with cellular and molecular alterations of the immune and inflammatory homeostasis that have been linked to the disorders that astronauts suffer from during their missions. Most of the research of the past 30 years has consistently established that innate adaptive immune cells represent a target of microgravity, which leads to their defective or dysfunctional activation, as well as to an altered ability to produce soluble mediators-e.g., cytokines/chemokines and bioactive lipids-that altogether control tissue homeostasis. Bioactive lipids include a vast array of endogenous molecules of immune origin that control the induction, intensity and outcome of the inflammatory events. However, none of the papers published so far focus on a newly characterized class of lipid mediators called specialized pro-resolving mediators (SPMs), which orchestrate the "resolution of inflammation"-i.e., the active control and confinement of the inflammatory torrent mostly driven by eicosanoids. SPMs are emerging as crucial players in those processes that avoid acute inflammation to degenerate into a chronic event. Given that SPMs, along with their metabolism and signaling, are being increasingly linked to many inflammatory disorders, their study seems of the outmost importance in the research of pathological processes involved in space-related diseases, also with the perspective of developing therapeutic countermeasures. Here, we show that microgravity, simulated in the rotary cell culture system (RCCS) developed by NASA, rearranges SPM receptors both at the gene and protein level, in human monocytes but not in lymphocytes. Moreover, RCCS treatment reduces the biosynthesis of a prominent SPM like resolvin (Rv) D1. These findings strongly suggest that not only microgravity can impair the functioning of immune cells at the level of bioactive lipids directly involved in proper inflammation, but it does so in a cell-specific manner, possibly perturbing immune homeostasis with monocytes being primary targets.

[Informatics support for risk assessment and identification of preventive measures in small and micro-enterprises: occupational hazard datasheets]. / II supporto informativo alla valutazione dei rischi ed alla individuazione delle misure preventive nelle piccole e micro imprese: le schede di rischio professionale.

BACKGROUND: Risk assessment is the fundamental process of an enterprise's prevention system and is the principal mandatory provision contained in the Health and Safety Law (Legislative Decree 81/2008) amended by Legislative Decree 106/2009. In order to properly comply with this obligation also in small-sized enterprises, the appropriate regulatory bodies should provide the enterprises with standardized tools and methods for identifying, assessing and managing risks. OBJECTIVES: To assist in particular small and micro-enterprises (SMEs) with risk assessment, by providing a flexible tool that can also be standardized in the form of a datasheet, that can be updated with more detailed information on the various work contexts in Italy. METHODS: Official efforts to provide Italian SMEs with information may initially make use of the findings of research conducted by ISPESL over the past 20 years, thanks in part to cooperation with other institutions (Regions, INAIL-National Insurance Institute for Occupational Accidents and Diseases), which have led to the creation of an information system on prevention consisting of numerous databases, both statistical and documental ("National System of Surveillance on fatal and serious accidents", "National System of Surveillance on work-related diseases", "Sector hazard profiles" database, "Solutions and Best Practices" database, "Technical Guidelines" database, "Training packages for prevention professionals in enterprises" database). With regard to evaluation criteria applicable within the enterprise, the possibility of combining traditional and uniform areas of assessment (by sector or by risk factor) with assessments by job/occupation has become possible thanks to the cooperation agreement made in 2009 by ISPESL, the ILO (International Labour Organisation) of Geneva and IIOSH (Israel Institute for Occupational Health and Hygiene) regarding the creation of an international Database (HDODB) based on risk datasheets per occupation. The project sets out to assist in particular small and micro-enterprises with risk assessment, providing a flexible and standardized tool in the form of a datasheet, that can be updated with more detailed information on the various work contexts in Italy. RESULTS: The model proposed by ISPESL selected the ILO's "Hazard Datasheet on Occupation" as an initial information tool to steer efforts to assess and manage hazards in small and micro-enterprises. In addition to being an internationally validated tool, the occupation datasheet has a very simple structure that is very effective in communicating and updating information in relation to the local context. CONCLUSIONS: According to the logic based on the providing support to enterprises by means of a collaborative network among institutions, local supervisory services and social partners, standardised hazard assessment procedures should be, irrespective of any legal obligations, the preferred tools of an "updatable information system" capable of providing support for the need to improve the process of assessing and managing hazards in enterprises.