Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.

The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis.

The mechanisms underlying the pathogenesis of rheumatoid arthritis (RA) involve different components of the immune system. In subjects with genetic predisposition to develop RA, a tight interaction between cells and mediators of the innate and adaptive immune system leads to the amplification and perpetuation of inflammation and tissue remodelling. The research carried out in the last year in the field of RA has improved the current knowledge on the pathogenesis of the disease, and is potentially useful to develop new therapeutic approaches. Thus, in this review we provide an overview on the new insights into RA pathogenesis, resulting from a literature search of the data published in the last year.

/pdf/pathogenesis-of-rheumatoid-arthritis-one-year-in-review-2022-1oz167xn.pdf

Pathogenesis of rheumatoid arthritis: one year in review 2022.

Adipokines are adipose tissue-derived factors not only playing an important role in metabolism but also influencing other central processes of the body, such as inflammation. In autoimmune diseases, adipokines are involved in inflammatory pathways affecting different cell types. Many rheumatic diseases belong to the group of autoimmune diseases, for example rheumatoid arthritis (RA) and psoriatic arthritis. Due to the autoimmune responses, a chronic inflammatory milieu develops, which affects the whole body, including adipose tissue. Metabolic alterations such as obesity influence inflammatory responses in autoimmune diseases. Adipokines are bioactive mediators mainly produced by adipose tissue. Due to alterations of systemic adipokine levels, their role as biomarkers with diagnostic potential has been suggested in the context of rheumatic diseases. In the affected joints of RA patients, different synoviocytes but also osteoclasts, osteoblasts, and chondrocytes produce several adipokines, contributing to the unique inflammatory microenvironment. Adipokines have been shown to be potent modulatory effectors on different cell types of the immune system but also local cells in synovial tissue, cartilage, and bone. This review highlights the most recent findings on the role of adipokines in the pathophysiology of inflammatory arthritis with a distinct focus on RA in the quickly developing research field.

https://www.mdpi.com/2073-4409/10/2/216/pdf

Adipokines and Autoimmunity in Inflammatory Arthritis

Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, is a type I single transmembrane protein mainly expressed in myeloid cells, such as monocytes, macrophages, glial cells, and osteoclasts. The endogenous ligands, colony-stimulating factor-1 (CSF-1) and Interleukin-34 (IL-34), activate CSF-1R and downstream signaling pathways including PI3K-AKT, JAK-STATs, and MAPKs, and modulate the proliferation, differentiation, migration, and activation of target immune cells. Over the past decades, the promising therapeutic potential of CSF-1R signaling inhibition has been widely studied for decreasing immune suppression and escape in tumors, owing to depletion and reprogramming of tumor-associated macrophages. In addition, the excessive activation of CSF-1R in inflammatory diseases is consecutively uncovered in recent years, which may result in inflammation in bone, kidney, lung, liver and central nervous system. Agents against CSF-1R signaling have been increasingly investigated in preclinical or clinical studies for inflammatory diseases treatment. However, the pathological mechanism of CSF-1R in inflammation is indistinct and whether CSF-1R signaling can be identified as biomarkers remains controversial. With the background information aforementioned, this review focus on the dialectical roles of CSF-1R and its ligands in regulating innate immune cells and highlights various therapeutic implications of blocking CSF-1R signaling in inflammatory diseases. 

Targeting CSF-1R represents an effective strategy in modulating inflammatory diseases.

Coupling between osteogenesis and angiogenesis determines bone morphology A decrease in the osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) is one of the underlying causes of senile osteoporosis (OP) Here, we investigated the involvement of circular RNAs (circRNAs) in the osteogenic differentiation of BMSCs and the pathogenesis of senile OP We sequenced RNA and found decreases expression of hsa_circ_0006215 in BMSCs from patients with OP We further assessed the role of hsa_circ_0006215 in the osteogenic differentiation of BMSCs using lentivirus-mediated hsa_circ_0006215 overexpression and knockdown Overexpression of hsa_circ_0006215 promoted the osteogenic differentiation of BMSCs Luciferase reporter and RNA pull-down assays revealed that hsa_circ_0006215 bound to miRNA-942-5p and thus regulated RUNX2 and vascular endothelial growth factor (VEGF) expression in BMSCs We assessed osteogenesis and vascular coupling in co-cultured cells, and the role of hsa_circ_0006215 in bone formation in vivo using a cortical bone defect model We found that hsa_circ_0006215 promoted bone defect repair Overall, our results showed that hsa_circ_0006215 has an important function in osteogenesis and could be a novel target for treating senile OP

CircRNA hsa_circ_0006215 promotes osteogenic differentiation of BMSCs and enhances osteogenesis-angiogenesis coupling by competitively binding to miR-942-5p and regulating RUNX2 and VEGF.

Adiponectin (APN) belongs to adipokines. Previous studies showed contradictory results that have both proinflammatory and anti-inflammatory effects in rheumatoid arthritis (RA). We set out to detect the levels of APN and the correlations between APN and the clinical manifestations in RA patients. Sera of 60 newly diagnosed patients with RA and 29 age- and gender-matched healthy subjects were collected. Clinical parameters, including C-reactive protein (CRP), erythrocyte sedimentation rate, rheumatoid factor (RF), antibodies to cyclic citrullinated peptide, disease activity score 28, and bone erosion conditions, were collected. The serum levels of total APN and high-molecular-weight APN (HMW-APN) were detected by enzyme-linked immunosorbent assay. As a result, total APN and HMW-APN levels were all lower in patients with RA compared with healthy controls. The levels of APN and HMW-APN were all positively correlated with CRP levels. There was also positive correlation between HMW-APN levels and RF levels. Moreover, patients with higher disease activities had higher HMW-APN levels; patients with more severe synovial thickening had higher APN and HMW-APN levels. Therefore, APN, especially HMW-APN, may play a regulatory role in RA.

Association Between Adiponectin and Clinical Manifestations in Rheumatoid Arthritis.

Background: Interleukin (IL)-34 is a new pro-inflammatory cytokine. Previous studies showed that IL-34 plays a key role in inflammation and osteoporosis in rheumatoid arthritis (RA). However, wheth...

Effect of Interleukin-34 on Secretion of Angiogenesis Cytokines by Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis

To detect the effect of interleukin (IL)-34 on the secretion of Receptor activator of nuclear factor kappa-B ligand (RANKL)/Osteoprotegerin (OPG) and Matrix metalloproteinase (MMP)-3 by fibroblast-like synoviocytes (FLS) and peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and to investigate whether the effect is mediated by IL-17. RA-FLS and RA-PBMCs were stimulated with recombinant human (rh) IL-34, with or without the IL-17 inhibitor Plumbagin. The supernatant of the culture medium was collected and the levels of RANKL, OPG, and MMP-3 were detected by enzyme-linked immunosorbent assay (ELISA). RhIL-34 promoted RANKL secretion and inhibited OPG secretion in RA-FLS. The effect was weakened by the addition of the IL-17 inhibitor. In contrast, rhIL-34 had no significant effect on MMP-3 secretion by FLS. RhIL-34 elevated the secretion of RANKL by RA-PBMCs but not by healthy-PBMCs. Furthermore, the secretion of RANKL by RA-PBMCs reduced after the addition of the IL-17 inhibitor. OPG secretion by both RA-FLS and FLS from healthy controls was inhibited by rhIL-34, but were elevated after the addition of the IL-17 inhibitor. RhIL-34 had no significant effect on MMP-3 secretion by both RA-PBMCs and healthy-PBMCs. IL-34 enhances RANKL/OPG expression by RA-FLS and RA-PBMCs, and this effect is, indirectly, mediated by IL-17. This cytokine is therefore likely to to play an important role in local joint destruction and systemic osteoporosis in RA, and is therefore a potential therapeutic target for the treatment of this disease.

Effects of IL-34 on the secretion of RANKL/OPG by fibroblast-like synoviocytes and peripheral blood mononuclear cells in rheumatoid arthritis.

To measure the serum levels of anticarbamylated protein (CarP) antibodies in patients with rheumatoid arthritis (RA) in China and to evaluate the association of anti-CarP antibodies with clinical parameters and disease activity. 260 Chinese patients with RA, 40 patients with osteoarthritis (OA), 88 patients with spondyloarthritis (SpA) and 77 healthy controls were included. The serum levels of anti-CarP antibodies were detected by ELISA. Blood tests to detect the anticyclic citrullinated peptide (CCP) antibody level, rheumatoid factor (RF) level, erythrocyte sedimentation rate, C reactive protein level and Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) were performed by standard methods. Bone erosion was assessed by colour Doppler ultrasonography. A total of 18.8% of patients with RA and 9.4% of anti-CCP antibody and RF-double-negative patients were positive for anti-CarP antibody. The anti-CarP antibody level was significantly higher in patients with RA than in patients with OA or SpA and in healthy controls. Univariate and multivariate analyses showed that the level of anti-CarP antibody was positively correlated with DAS28-ESR; the higher a level of serum anti-CarP antibody, the higher the DAS28-ESR score. Anti-CarP-positive patients had higher disease activity scores than anti-CarP-negative patients. Moreover, anti-CarP-positive patients had a higher risk of developing bone erosion. The anti-CarP antibody was found to play an important role in the diagnosis of RA, especially in anti-CCP antibody and RF-double-negative patients. The anti-CarP antibody is a potential marker of disease activity and bone erosion in RA.

https://jim.bmj.com/content/jim/68/6/1186.full.pdf

Elevated levels of anti-carbamylated protein antibody in patients with rheumatoid arthritis: association with disease activity and bone destruction.

Objectives: To investigate the application effect of mixed reality (MR) holographic imaging technology in the clinical surgical treatment of spinal cord glioma. Methods: The clinical data of 53 patients with spinal cord glioma who underwent surgical treatment in the Neurosurgery Department of our hospital from January 2017 to May 2020 were retrospectively studied. All the patients were divided into two groups according to different assistive technologies during the surgery: the observation group and the control group, with 30 cases and 23 cases respectively. Patients in the observation group received MR holographic imaging technology intraoperatively, while those in the control group received ultrasound. The surgical conditions of the two groups: the rate of complete resection of tumor lesions and the evaluation accuracy of complete resection were compared. Patients were followed up for 12 months in the outpatient department after surgery, and the recovery of postoperative spinal physiological function was evaluated based on imaging review and MMS scale grading, and the recurrence was obtained. Results: There was no statistical significance in the basic clinical conditions between the two groups (P>0.05), and the total tumor resection rate in the experimental group was 96.67%, and that in the control group was 82.61%, showing a statistically significant difference (P<0.05). Based on enhanced MRI examination as the standard, the evaluation accuracy of intraoperative complete tumor resection in the experimental group was 93.33%, significantly higher than that in the control group (73.54%), with a statistical significance (P<0.05). The incidence of postoperative complications was 3.33% in the experimental group and 21.74% in the control group, with a statistically significant difference (P<0.05). Postoperative follow-up showed that good recovery rate of spinal cord function in the experimental group was 56.70%, and that in the control group was 41.09%, with a statistically significant difference (P<0.05). The recurrence rate was 0 in the experimental group and 4.34% in the control group at follow-up, with no statistically significant difference (P>0.05). Conclusions: With the application of MR holographic imaging technology in the surgical treatment of spinal cord glioma, critical clinical value can be realized. Specifically, the resection degree of spinal cord glioma can be displayed in real time, accurately, and three-dimensionally, the effect of surgical resection can be improved, surgical complications can be diminished, and the recovery of spinal cord function can be accelerated.

/pdf/application-evaluation-of-mixed-reality-holographic-imaging-1wjy0385.pdf

Application evaluation of mixed-reality holographic imaging technology in the surgical treatment of spinal cord glioma

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