Long non-coding RNA fine-tunes bone homeostasis and repair by orchestrating cellular crosstalk and β-catenin-OPG/Jagged1 pathway.

The IncRNA was initially believed to be dispensable for physiology due to the lack of observable phenotypes in knockout (KO) mice. However, our study challenges this conclusion. We found that both KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis.

Mechanosensing regulates pDC activation in the skin through NRF2 activation.

Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs.

Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that has a strong female predominance. Both the X-linked TLR7 and TLR8 can induce type I IFN (IFN-I) by plasmacytoid DCs (pDCs), which can promote fibrosis. We identified five subclusters of pDCs, including ISGhigh clusters that were over-represented in SSc patients.

Cellular signatures in human blood track bone mineral density in postmenopausal women.

Osteoclasts are the sole bone-resorbing cells and are formed by the fusion of osteoclast precursor cells (OCPs) derived from myeloid lineage cells. Animal studies reveal that circulating OCPs (cOCPs) in blood travel to bone and fuse with bone-resident osteoclasts. However, the characteristics of human cOCPs and their association with bone diseases remain elusive.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8 T cells. However, the mechanisms that govern this immunometabolic axis remain unexplored.

SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion.

Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss.

Reciprocal suppression between TGFβ signaling and TNF stimulation finetunes the macrophage inflammatory response.

Inflammation plays a crucial role in the development of various disease conditions or is closely associated with them. Inflammatory cytokines like TNF often engage in interactions with other cytokines and growth factors, including TGFβ, to orchestrate inflammatory process. Basal/endogenous TGFβ signaling is a universal presence, yet the precise way TNF communicates with TGFβ signaling to regulate inflammation and influence inflammatory levels in macrophages has remained elusive.

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers.

Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors.

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge.

Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity.

The discovery of toll-like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA-containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN-I), are providing critical insights relevant to TLR-mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases.

RBP-J regulates homeostasis and function of circulating Ly6C monocytes.

Notch-RBP-J signaling plays an essential role in the maintenance of myeloid homeostasis. However, its role in monocyte cell fate decisions is not fully understood. Here, we showed that conditional deletion of transcription factor RBP-J in myeloid cells resulted in marked accumulation of blood Ly6C monocytes that highly expressed chemokine receptor CCR2.

Long non-coding RNA Malat1 fine-tunes bone homeostasis and repair by orchestrating cellular crosstalk and the β-catenin-OPG/Jagged1 pathway.

The IncRNA Malat1 was initially believed to be dispensable for physiology due to the lack of observable phenotypes in Malat1 knockout (KO) mice. However, our study challenges this conclusion. We found that both Malat1 KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis.

Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 T cells. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored.

New Horizons: Translational Aspects of Osteomorphs.

Osteomorphs are a newly described osteoclast lineage cell in mice, which are suggested to play a significant role in the maintenance of bone resorption. Preclinical investigations revealed that osteomorphs are generated through the fission of multinucleated bone-resorbing osteoclasts and can also re-fuse with existing osteoclasts. Modifications to RANKL signaling have been shown to alter cycles of fission and re-fusion of osteomorphs in mice.

Optineurin regulates osteoblast function in an age-dependent fashion in a mouse model of Paget's disease of bone.

Paget's disease of bone (PDB) is a degenerative disorder affecting the skull and bones. Hyperactive osteoclasts (OCs) initiate bone degradation in the early stage, followed by increased bone formation by osteoblasts (OBs) in trabecular bones during the advanced stage. This OB-OC uncoupling results in bone deformations and irregular trabecular bone patterns.

TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance.

Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides.

Jagged1 Acts as an RBP-J Target and Feedback Suppresses TNF-Mediated Inflammatory Osteoclastogenesis.

TNF plays a crucial role in inflammation and bone resorption in various inflammatory diseases, including rheumatoid arthritis (RA). However, its direct ability to drive macrophages to differentiate into osteoclasts is limited. Although RBP-J is recognized as a key inhibitor of TNF-mediated osteoclastogenesis, the precise mechanisms that restrain TNF-induced differentiation of macrophages into osteoclasts are not fully elucidated.

Dichotomous roles of RIPK3 in regulating the IFN response and NLRP3 inflammasome in human monocytes.

Regulation of the profile and magnitude of toll-like receptor (TLR) responses is important for effective host defense against infections while minimizing inflammatory toxicity. The chemokine CXCL4 regulates the TLR8 response to amplify inflammatory gene and inflammasome activation while attenuating the interferon (IFN) response in primary monocytes. In this study, we describe an unexpected role for the kinase RIPK3 in suppressing the CXCL4 + TLR8-induced IFN response and providing signal 2 to activate the NLRP3 inflammasome and interleukin (IL)-1 production in primary human monocytes.

Origin of Osteoclasts: Osteoclast Precursor Cells.

Osteoclasts are multinucleated bone-resorbing cells and a key player in bone remodeling for health and disease. Since the discovery of osteoclasts in 1873, the structure and function of osteoclasts and the molecular and cellular mechanisms of osteoclastogenesis have been extensively studied. Moreover, it has been well established that osteoclasts are differentiated in vitro from myeloid cells such as bone marrow macrophages or monocytes.

Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis.

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood.

Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass.

M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages, and osteoclasts. Tissue-resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in the bone marrow produce M-CSF to maintain myeloid homeostasis.