Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin β3. We have previously shown that TG2−/− mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bound form promotes phagocytosis. Besides being a binding partner for integrin β3, a receptor known to mediate the uptake of apoptotic cells via activating Rac1, we also show that TG2 binds MFG-E8 (milk fat globulin EGF factor 8), a protein known to bridge integrin β3 to apoptotic cells. Finally, we report that in wild-type macrophages one or two engulfing portals are formed during phagocytosis of apoptotic cells that are characterized by accumulation of integrin β3 and Rac1. In the absence of TG2, integrin β3 cannot properly recognize the apoptotic cells, is not accumulated in the phagocytic cup, and its signaling is impaired. As a result, the formation of the engulfing portals, as well as the portals formed, is much less efficient. We propose that TG2 has a novel function to stabilize efficient phagocytic portals.
Activation of vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D 3 (1,25-vitD) reprograms dendritic cells (DC) to become tolerogenic.Previous studies suggested that 1,25-vitD could inhibit the changes brought about by differentiation and maturation of DCs. Underpinning the described phenotypic and functional alterations, there must be 1,25-vitD-coordinated transcriptional events. However, this transcriptional program has not been systematically investigated, particularly not in a developmental context. Hence, it has not been explored how 1,25-vitD-regulated genes, particularly the ones bringing about the tolerogenic phenotype, are connected to differentiation. We conducted global gene expression analysis followed by comprehensive quantitative PCR validation to clarify the interrelationship between 1,25-vitD and differentiation-driven gene expression patterns in developing human monocyte-derived and blood myeloid DCs. In this study we show that 1,25-vitD regulates a large set of genes that are not affected by differentiation. Interestingly, several genes, impacted both by the ligand and by differentiation, appear to be regulated by 1,25-vitD independently of the developmental context. We have also characterized the kinetics of generation of 1,25-vitD by using three early and robustly regulated genes, the chemokine CCL22, the inhibitory receptors CD300LF and CYP24A1. We found that monocyte-derived DCs are able to turn on 1,25-vitD sensitive genes in early phases of differentiation if the precursor is present. Our data collectively suggest that exogenous or endogenously generated 1,25-vitD regulates a large set of its targets autonomously and not via inhibition of differentiation and maturation, leading to the previously characterized tolerogenic state. D endritic cells (DCs)4 are conductors of the adaptive immune system (1, 2). In their immature form (immature DCs, IDCs), they act as sentinels and constantly monitor the tissue they reside in. If DCs sense an abnormal state by detecting pathogens, endogenous factors released by necrotic cells, or inflammatory cytokines, they mature. Maturation is characterized by the migration of DCs to lymphoid organs, the down-regulation of Ag uptake, and an enhanced capacity for priming naive T cells (1, 2). The interaction between DCs, T cells, and environmental cues will dictate whether an immune response is mounted or whether tolerance is established or maintained. DCs are inherently heterogeneous, as they need to respond to a variety of signals in very different contexts. The integration of signals will lead to at least two distinct, e.g., immunogenic or tolerogenic, DC immunophenotypes. How these stereotypic immunophenotypes are achieved at the transcriptional level is not well understood. Nuclear hormone receptors, a group of lipid-activated transcription factors, have been increasingly implicated in this process (3).A member of this family is the vitamin D receptor (VDR). A number of studies (4 -10) provided evidence that the addition of the active form of vitamin D 3 ,...
Brown and beige adipocytes contribute significantly to the regulation of whole body energy expenditure and systemic metabolic homeostasis not exclusively by thermogenesis through mitochondrial uncoupling. Several studies have provided evidence in rodents that brown and beige adipocytes produce a set of adipokines ("batokines") which regulate local tissue homeostasis and have beneficial effects on physiological functions of the entire body. We observed elevated secretion of Interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, but not tumor necrosis factor alpha (TNFα) or IL-1β pro-inflammatory cytokines, by ex vivo differentiating human beige adipocytes (induced by either PPARγ agonist or irisin) compared to white. Higher levels of IL-6, IL-8 and MCP-1 were released from human deep neck adipose tissue biopsies (enriched in browning cells) than from subcutaneous ones. IL-6 was produced in a sustained manner and mostly by the adipocytes and not by the undifferentiated progenitors. Continuous blocking of IL-6 receptor by specific antibody during beige differentiation resulted in downregulation of brown marker genes and increased morphological changes that are characteristic of white adipocytes. The data suggest that beige adipocytes adjust their production of IL-6 to reach an optimal level for differentiation in the medium enhancing browning in an autocrine manner.
Promyelocytic NB4 leukemia cells undergo differentiation to granulocytes following retinoic acid treatment. Here we report that tissue transglutaminase (TG2), a protein cross-linking enzyme, was induced, then partially translocated into the nucleus, and became strongly associated with the chromatin during the differentiation process. The transglutaminase-catalyzed cross-link content of both the cytosolic and the nuclear protein fractions increased while NB4 cells underwent cellular maturation. Inhibition of cross-linking activity of TG2 by monodansylcadaverin in these cells led to diminished nitroblue tetrazolium (NBT) positivity, production of less superoxide anion, and decreased expression of GP91PHOX, the membrane-associated subunit of NADPH oxidase. Neutrophils isolated from TG2 ؊/؊ mice showed diminished NBT reduction capacity, reduced superoxide anion formation, and down-regulation of the gp91phox subunit of NADPH oxidase, compared with wild-type cells. It was also observed that TG2 ؊/؊ mice exhibited increased neutrophil phagocytic activity, but had attenuated neutrophil chemotaxis and impaired neutrophil extravasation with higher neutrophil counts in their circulation during yeast extract-induced peritonitis. These results clearly suggest that TG2 may modulate the expression of genes related to neutrophil functions and is involved in several intracellular and extracellular functions of extravasating neutrophil. ( IntroductionTransglutaminases are a family of Ca 2ϩ -dependent enzymes that can mediate covalent cross-linking of proteins by forming isodipeptide bonds between glutamines and the ⑀-amino groups of lysine residues (transglutamylation). 1 Several distinct transglutaminases have been described in vertebrates. Among them, TG2, also referred to as tissue transglutaminase, is a multifunctional protein and the only member of the transglutaminase family expressed in a wide variety of tissues and cell types. 2 In addition to cross-linking protein, TG2 can modify proteins by amine incorporation, deamination, and by acting as an isopeptidase in a Ca 2ϩ -dependent manner. 3 Although TG2 cross-links several intracellular and extracellular proteins, the biologic significance of its enzymatic functions is still far from being completely understood. It has been shown in several experimental models that TG2 facilitates apoptosis and clearance of dead cells in response to stimuli that result in its increased expression and activation of transamidating activity. 3 TG2 is also known as a cell surface adhesion mediator. Integrin-bound TG2 on the cell surface provides a binding site for fibronectin and facilitates adhesion and spreading of cells. 4,5 It plays a significant role in wound healing and angiogenesis, as well as in the assembly, remodeling, and stabilization of the extracellular matrix in various tissues. 6,7 The GTP-binding form of TG2, which mediates intracellular signaling by ␣1B and ␣1D adrenergic receptors, has a signaling function apart from its transamidating activity. 8,9 Data suggest that TG2 d...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.