Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains ...highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated “terminal selectors.” Using BM chimeras, conditional Irf8fl/fl mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.
Display omitted
•IRF8 is dispensable for survival of terminally differentiated monocytes•IRF8 is a terminal selector of the cDC1 lineage•IRF8 is not intrinsically required for pDC development•IRF8 controls several functional modules in differentiated pDCs
IRF8 has been proposed to be essential for the development of monocytes, pDCs, and cDC1s. By using several conditional Irf8-deficient mice, Sichien et al. demonstrate that IRF8 is dispensable for monocyte development after the cMoP stage. Moreover, they show that IRF8 is required for the survival and function of cDC1s and pDCs, respectively.
Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)–rich environment with protection has ...remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)–induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction.
Highlights • Innate cells contribute to the development of asthma features. • Epithelial cell–DC crosstalk is crucial for asthma development. • Epithelium-derived cytokines contribute to ILC2 ...responses. • Basophils have no role in Th2 sensitization to HDM, but contribute to the effector phase.
High mobility group box 1 (HMGB1) is a molecular alarm signal that triggers an immune response when released. It was assumed that the receptor for advanced glycation end‐products (RAGE) would mediate ...the signal to the immune system. Recently pattern recognition receptors that are triggered by molecules of bacterial origin (the Toll‐like receptor (TLR) family) were shown to also respond to HMGB1. Now two papers establish the TLR4–HMGB1 axis as proinflammatory, eventually leading to disparate conditions like seizures or skin cancer. These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1.
Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b+ ...monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b+ cDCs but not CD103+ cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l−/− mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b+ cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.
▸ CD64 and MAR-1 are optimum markers for separating moDCs from cDCs ▸ CD11b+ cDCs, not CD103+ cDCs, induce Th2 cell priming in lung ▸ moDCs, not cDCs, are the source of proinflammatory chemokines ▸ moDCs are not the exclusive APC for Th1 cell induction
Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (
Tnfaip3) determines the activation threshold of DCs, via control of canonical ...NF-κB activation.
Tnfaip3
fl/fl
Cd11c-
cre
+ mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly—features of systemic lupus erythematosus—and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in
TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
► A20 deficiency in DCs causes systemic autoimmunity ► A20-deficient DCs stimulate plasma cell conversion in the absence of T cells ► A20 is proapoptotic in DCs ► A20-deficient DCs better capture and present apoptotic cells
Dendritic cells (DCs) play a pivotal role in the regulation of the immune response. DC development and activation is finely orchestrated through transcriptional programs. GATA1 transcription factor ...is required for murine DC development, and data suggest that it might be involved in the fine-tuning of the life span and function of activated DCs. We generated DC-specific Gata1 knockout mice (Gata1-KO
), which presented a 20% reduction of splenic DCs, partially explained by enhanced apoptosis. RNA sequencing analysis revealed a number of deregulated genes involved in cell survival, migration, and function. DC migration toward peripheral lymph nodes was impaired in Gata1-KO
mice. Migration assays performed in vitro showed that this defect was selective for CCL21, but not CCL19. Interestingly, we show that Gata1-KO
DCs have reduced polysialic acid levels on their surface, which is a known determinant for the proper migration of DCs toward CCL21.
To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA).
Patients with axSpA from the Rheumatic ...Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models.
In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 95%CI 1.9; 27.7), adverse events (OR 9.1 2.5; 33.3), or other reasons (OR 7.7 1.6; 37.9) compared to primary failure.
Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.
The use of pumps working as turbines (PATs) is a sustainable technical measure that contributes to the improvement of energy efficiency in water systems. However, its performance analysis in off-grid ...recovery systems is a complex task that must consider both hydraulic (PAT) and electrical machines (typically a self-excited induction generator-SEIG). Aside from several kinds of research that analyze the PAT-SEIG behavior under steady-state constant hydraulic and electrical conditions, this research focuses on the analysis of PAT-SEIG transient regimes, by analyzing their variation when a sudden change occurs in the hydraulic or electrical components. Analytical models were developed to represent the operation of SEIG, PAT, and the PAT-SEIG coupled system. Hydraulic and electromechanical experimental tests validated these models. An excellent fit was obtained when analytical and experimental values were compared. With these models, the impact on the operation of the PAT-SEIG system was examined when sudden change occurred in the excitation capacitances, resistive loads, or recovered head. With a sudden increase of resistive load, the hydraulic power and SEIG stator current remain almost constant. However, there is an increase of SEIG reactive power, decreasing the PAT-SEIG efficiency. Also, with a sudden increase of SEIG capacitors or PAT hydraulic head, the SEIG stator current increases once and not again, while PAT-SEIG efficiency decreases, but the induction generator can be overloaded. The development of this research is key to the advancement of future models which can analyze the coupling of micro-hydropower solutions.
PDF
