Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the ...two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular ...and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
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•Synovial fibroblasts mediate tissue priming after repeated inflammatory challenge•Tissue priming depends on intracellular complement C3 and C3a receptor expression•Intracellular C3 and C3a receptor drive metabolic reprogramming of fibroblasts•A metabolic shift promotes inflammasome activation and protects from cell senescence
Inflammatory diseases typically involve recurrence and progressive worsening at specific predilection sites, but the underlying mechanisms remain unclear. Friščić et al. reveal that at the center of this inflammatory tissue priming are fibroblasts, which undergo metabolic reprogramming and a shift to a pro-inflammatory state including inflammasome activation.
Bone tissue undergoes permanent and lifelong remodeling with a concerted action of bone-building osteoblasts and bone-resorbing osteoclasts. A precise cooperation between those two cell types is ...critical in the complex process of bone renewal. Galectin-3 is a member of the β-galactoside-binding lectin family playing multiple roles in cell growth, differentiation and aggregation. As it has been described to be expressed in bone, galectin-3 might influence bone homeostasis by regulating the function and/or interplay of osteoblasts and osteoclasts. Here, we investigated the role of galectin-3 in osteoclastogenesis and osteoblast-osteoclast interactions. Bone histomorphometric analysis and μCT measurements revealed a decreased trabecular bone volume and an increased osteoclast number in 12weeks old male galectin-3 knockout mice compared to wildtype littermates. Galectin-3 deficient bone marrow cells displayed a higher osteoclastogenic capacity in ex vivo differentiation assays, associated with elevated TRAF6 mRNA levels, suggesting an intrinsic inhibition of osteoclastogenesis by galectin-3 interfering with RANKL-mediated signaling. Furthermore, the addition of extracellular galectin-3 to murine or human osteoclastogenesis assays inhibited osteoclast formation and osteoclast numbers were higher in co-culture assays with galectin-3 deficient osteoblasts. In conclusion, our data suggest the secretion of galectin-3 as a novel mechanism for osteoblasts to control osteoclastogenesis and to maintain trabecular bone homeostasis independently of the RANKL/OPG-axis.
•Galectin-3 regulates osteoclastogenesis independently of the RANK/OPG-axis.•Galectin-3 deficient mice exhibit a lowered trabecular bone volume with elevated osteoclast numbers.•Galectin-3 is important for osteoblast-osteoclast communication.
Proton-coupled monocarboxylate transporters (MCTs) are carriers of high-energy metabolites such as lactate, pyruvate, and ketone bodies and are expressed in most tissues. It has previously been shown ...that transport activity of MCT1 and MCT4 is enhanced by the cytosolic carbonic anhydrase II (CAII) independent of its catalytic activity. We have now studied the influence of the extracellular, membrane-bound CAIV on transport activity of MCT1/4, heterologously expressed in Xenopus oocytes. Coexpression of CAIV with MCT1 and MCT4 resulted in a significant increase in MCT transport activity, even in the nominal absence of CO2/HCO3−. CAIV-mediated augmentation of MCT activity was independent of the CAIV catalytic function, since application of the CA-inhibitor ethoxyzolamide or coexpression of the catalytically inactive mutant CAIV-V165Y did not suppress CAIV-mediated augmentation of MCT transport activity. The interaction required CAIV at the extracellular surface, since injection of CAIV protein into the oocyte cytosol did not augment MCT transport function. The effects of cytosolic CAII (injected as protein) and extracellular CAIV (expressed) on MCT transport activity, were additive. Our results suggest that intra- and extracellular carbonic anhydrases can work in concert to ensure rapid shuttling of metabolites across the cell membrane.
Background: Monocarboxylate transporters (MCTs) mediate the shuttling of high-energy metabolites between different cells.
Results: Transport activity of MCTs is augmented by intracellular and extracellular carbonic anhydrases (CAs).
Conclusion: Intracellular and extracellular CAs can work in concert to ensure rapid shuttling of metabolites across the cell membrane.
Significance: CAs play a pivotal role as regulators of metabolite transport in different tissues.
Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory ...molecules. Despite recent advances in the understanding on butyrophilins' role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation.
osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size.
steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.
Soluble cytosolic carbonic anhydrases (CAs) are well known to participate in pH regulation of the cytoplasm of mammalian cells. Membrane-bound CA isoforms—such as isoforms IV, IX, XII, XIV, and ...XV—also catalyze the reversible conversion of carbon dioxide to protons and bicarbonate, but at the extracellular face of the cell membrane. When human CA isoform IV was heterologously expressed in Xenopus oocytes, we observed, by measuring H⁺ at the outer face of the cell membrane and in the cytosol with ion-selective microelectrodes, not only extracellular catalytic CA activity but also robust intracellular activity. CA IV expression in oocytes was confirmed by immunocytochemistry, and CA IV activity measured by mass spectrometry. Extra- and intracellular catalytic activity of CA IV could be pharmacologically dissected using benzolamide, the CA inhibitor, which is relatively slowly membrane-permeable. In acute cerebellar slices of mutant mice lacking CA IV, cytosolic H⁺ shifts of granule cells following CO₂ removal/addition were significantly slower than in wild-type mice. Our results suggest that membrane-associated CA IV contributes robust catalytic activity intracellularly, and that this activity participates in regulating H⁺ dynamics in the cytosol, both in injected oocytes and in mouse neurons.
Tropical forests occupy small coral atolls to the vast Amazon basin. They occur across bioregions with different geological and climatic history. Differences in area and bioregional history shape ...species immigration, extinction and diversification. How this effects local diversity is unclear. The Indonesian archipelago hosts thousands of tree species whose coexistence should depend upon these factors. Using a novel dataset of 215 Indonesian forest plots, across fifteen islands ranging in area from 120 to 785 000 km2, we apply Gaussian mixed effects models to examine the simultaneous effects of environment, earthquake proximity, island area and bioregion upon tree diversity for trees ≥ 10 cm diameter at breast height. We find that tree diversity declines with precipitation seasonality and increases with island area. Accounting for the effects of environment and island area we show that the westernmost bioregion Sunda has greater local diversity than Wallacea, which in turn has greater local diversity than easternmost Sahul. However, when the model includes geological activity (here proximity to major earthquakes), bioregion differences are reduced. Overall, results indicate that multi‐scale, current and historic effects dictate tree diversity. These multi‐scale drivers should not be ignored when studying biodiversity gradients and their impacts upon ecosystem function.
Public servants are conditioned by perceptions about their jobs environments that can lead them to have less appreciation for their organizations. There are few studies that focus on a theoretical ...and practical understanding of the organizational environment as a factor that may lead public workers to low motivation and job satisfaction levels. We aim to explore organizational environment of Colombia’s public-sector entities as a key organizational aspect, considering the demographic characteristics of Colombian public servants. Through multivariate statistics we explore whether some demographic and organizational traits of public officials play a role on their appreciations of their organizational environments. To do so, we use data from a survey of the National Department of Statistics of Colombia, covering more than 6,000 public officials at the regional level. This article aims to inform practice since it provides empirical evidence about Colombia’s public organizations employees, suggesting that graduate middle professionals with more than six years of service, and technicians with more than twelve years of service tend to purport negative perceptions about the organizational environments of Colombian public organizations. Thus, seniority in Colombia appears to have a key role on such perceptions.
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