PU.1 controls fibroblast polarization and tissue fibrosis

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis

AbstractMicroglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.</jats:p

Macrophages inhibit Coxiella burnetii by the ACOD1 ‐itaconate pathway for containment of Q fever

Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis-aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/- mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever

Methodology of calculation of construction and hydrodynamic parameters of a foam layer apparatus for mass-transfer processes

Промислова реалізація методу стабілізації газорідинного шару дозволяє значно розширити галузь застосування пінних апаратів і відкриває нові можливості інтенсифікації технологічних процесів з одночасним створенням маловідходних технологій. У статті встановлені основні параметри, що впливають на гідродинаміку пінних апаратів, розглянуті основні конструкції та режими роботи пінних апаратів. Виявлено зв'язок гідродинамічних параметрів. Розглянуто гідродинамічні закономірності пінного шару. Вказані фактори, що впливають на процес масообміну, як в газовій, так і в рідкій фазах. Проведений аналіз ряду досліджень показав, що перспективним напрямком інтенсифікації процесу масообміну є розробка апаратів з трифазним псевдозрідженим шаром зрошуваної насадки складних форм із сітчастих матеріалів. Отже, необхідне проведення спеціальних досліджень гідродинамічних режимів роботи апарату з сітчастою насадкою і визначенням параметрів, що впливають на швидкість переходу насадки з одного режиму в інший.Industrial implementation of the stabilization method of the gas-liquid layer can significantly expand the field of use of foaming apparatus and opens up new opportunities for intensifying technological processes with the simultaneous creation of low-waste technologies. The article establishes the basic parameters influencing the hydrodynamics of foam apparatus, considers the basic constructions and operating modes of foam apparatus. The connection of hydrodynamic parameters is revealed. The hydrodynamic laws of the foam layer are considered. The indicated factors affecting the process of mass transfer, both in the gas and in the liquid phases. The conducted analysis of a number of studies showed that the perspective direction of intensification of the mass transfer process is the development of apparatuses with a three-phase fluidized bed of an irrigated nozzle of complex forms with mesh materials

Integrin-Alpha IIb Identifies Murine Lymph Node Lymphatic Endothelial Cells Responsive to RANKL

Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4+LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b+LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-β receptor signaling likewise regulated the proportion of ITGA2b+LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin

Beendigung der Entzündungsreaktion durch Interleukin-9 sezernierende angeborene Lymphozyten

Inflammation is the tightly controlled physiological process of activation of the body’s self-defence mechanisms. Dysbalanced inflammation leads to a misdirected self-defence and manifests as autoimmune disease, marked by a chronic inflammation and the destruction of the normal tissue physiology. This ultimately leads to the loss of the tissue’s functionality. Rheumatoid arthritis is one of the most chronic forms of inflammatory disease in humans. It affects roughly 1 % of the population world wide. Understanding the underlying mechanisms of chronic inflammation in rheumatoid arthritis is of pivotal clinical and socio-economic interest. Novel therapies and diagnostic biomarkers therefore are desirable. In this study, it was shown that interleukin-9 (IL-9) induced the resolution of inflammation by the activation and expansion of type 2 innate lymphoid cells (ILC2s). IL-9 was found to be an autocrine factor produced by ILC2s. The induction and activation of ILC2s by IL-9 positively affected the capacity of regulatory T cells. IL-9 up-regulated the expression of inducible T cell co-stimulator ligand (ICOS-L) and glucocorticoid-induced tumour necrosis factor-related ligand (GITR-L) on ILC2s. Engagement of the respective receptors on regulatory T cells promoted their activity and efficiently broke down the persistent inflammation. The data presented in this study highlight IL-9 as a checkpoint of inflammation control. In the murine system, the deficiency of IL-9 led to a persisting inflammatory arthritis, which was marked by the failure to resolve. Conversely, gene transfer therapy with Il9 enhanced the resolution of arthritis. In humans, ILC2s expressing IL-9 were specifically enriched in the synovial joint tissue of patients in a stable condition of disease inactivity, the so-called remission. The numbers of circulating ILC2s in the peripheral blood were predictive for the disease activity, as patients in remission displayed a particularly higher number of circulating ILC2s as compared to patients with a high disease activity. This highlighted the potential of ILC2s to serve as a novel biomarker in rheumatoid arthritis. In conclusion, gaining the control to induce the resolution of inflammation is not only relevant for numerous autoimmune disorders, but also for conditions of chronic infection. The current anti-rheumatic therapies exclusively suppress the activation pathways of inflammation. IL-9 driven activation of ILC2s and the subsequent boost of regulatory T cells hence describes a novel therapeutic concept, which fosters the activation of the resolution inducing pathways, rather than suppressing the pro-inflammatory cascades.Die Aktivierung der körpereigenen Selbstverteidigungsmechanismen, auch Entzündung genannt, ist ein streng kontrollierter physiologischer Prozess. Eine aus der Balance geratene Entzündungsreaktion kann zu einer unkontrollierten Attacke gegen den eigenen Körper führen. Man spricht dann von einer sogenannten Autoimmunerkrankung. Autoimmunerkrankungen verlaufen zumeist chronisch und durch die persistierende Entzündungsreaktion wird mit der Zeit das betroffene Gewebe zerstört. Dadurch wird dessen physiologische Funktionsfähigkeit beeinträchtigt und geht letztlich verloren. Rheumatoide Arthritis ist eine prototypische chronische Autoimmunerkrankung des Menschen, die etwa 1 % der weltweiten Bevölkerung betrifft. Es ist daher nicht nur von größter klinischer Bedeutung, sondern auch im sozio-ökonomischem Interesse, die Mechanismen, die dieser Erkrankung zugrunde liegen, zu verstehen. Ziel ist es daher, das Wissen um die Krankheitsmechanismen zu vertiefen und ein besseres Verständnis dafür zu entwickeln, warum die Entzündung persistiert und wie sie beendet werden kann. Dies erlaubte einerseits die Entwicklung neuer diagnostischer Biomarker, andererseits wäre auch die Entwicklung komplett neuer Therapieansätze möglich. In dieser Studie wurde dargelegt, wie das Zytokin Interleukin-9 (IL-9) durch die Aktivierung von Typ 2 angeborenen Lymphozyten (engl. type 2 innate lymphoid cells, ILC2s) die Beendigung einer chronischen Entzündungsreaktion einleiten kann. IL-9 agierte dabei als ein autokriner Faktor, der sowohl von ILC2s produziert wurde, als auch proliferativ und aktivierend auf diese wirkte. Aktivierte ILC2s exprimierten Rezeptorliganden, die wiederum regulatorische T Zellen aktivieren konnten. Diese Liganden (-L) waren ICOS-L und GITR-L (engl. für inducible T cell co-stimulator und glucocorticoid-induced tumour necrosis factor-related). Regulatorische T Zellen wurden also durch die ILC2-vermittelte Aktivierung in die Lage versetzt, die Beendigung der persistierenden Entzündungsreaktion einzuleiten. IL-9 konnte somit als zentraler Schalter in der Entzündungskontrolle etabliert werden. Im Mausmodell konnte gezeigt werden, dass das Fehlen dieses Zytokins zu einer chronisch persistierenden Arthritis führte. Umgekehrt konnte der Gentransfer von Il9, als therapeutischer Ansatz, die Beendigung der Entzündungsreaktion einleiten. Im Menschen reicherten sich IL-9 sezernierende ILC2s besonders in den Gelenken derjenigen Patienten an, die sich in einer Phase klinisch unauffälliger rheumatoiden Arthritis befanden, also in sogenannter Remission waren. Da die Anzahl der ILC2s im Blut mit der Aktivität der Erkrankung korrelierte, könnte die Anzahl der zirkulierenden ILC2s zukünftig als diagnostischer Biomarker genutzt werden. Schlussendlich ist es nicht nur für Autoimmunerkrankungen, sondern auch bei chronischen Infektionserkrankungen von zentraler Bedeutung die Mechanismen der chronischen Entzündungsreaktion zu entschlüsseln und Wege zu finden, diese zu beenden. Aktuell zielen anti-rheumatische Therapien lediglich darauf ab, die entzündungsfördernden Signalwege zu blockieren. Die Aktivierung von ILC2s durch IL-9 fördert im Gegensatz dazu pro-aktiv die Entzündungskontrolle und stellt somit ein neues Therapiekonzept dar

PU.1 controls fibroblast polarization and tissue fibrosis

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs