scholarly journals Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF

2022 ◽  
Vol 5 (4) ◽  
pp. e202101315
Author(s):  
Stefanie Dichtl ◽  
David E Sanin ◽  
Carolin K Koss ◽  
Sebastian Willenborg ◽  
Andreas Petzold ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protective Effects ◽  
M2 Macrophages ◽  
Time Resolved ◽  
Jnk Signaling ◽  
Macrophage Activity ◽  
Mechanistic Basis ◽  
Context Specific ◽  
And Function

Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternative-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balance of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages, we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis, and signaling pathway deconvolution. We found that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way, dependent on JNK signaling via the type 1 TNF receptor on specific populations of alternative-activated macrophages. We further determined that JNK signaling has a profound and broad effect on activated macrophage gene expression. Our findings suggest that TNF’s anti-M2 effects evolved to specifically modulate components of tissue and reparative M2 macrophages and TNF is therefore a context-specific modulator of M2 macrophages rather than a pan-M2 inhibitor.

Congenital pseudarthrosis of neurofibromatosis type 1: Impaired osteoblast differentiation and function and altered NF1 gene expression

Bone ◽  
2009 ◽  
Vol 44 (2) ◽  
pp. 243-250 ◽  
Author(s):  
Hannu-Ville Leskelä ◽  
Tommi Kuorilehto ◽  
Juha Risteli ◽  
Jussi Koivunen ◽  
Marja Nissinen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neurofibromatosis Type 1 ◽  
Osteoblast Differentiation ◽  
Neurofibromatosis Type ◽  
Congenital Pseudarthrosis ◽  
Nf1 Gene ◽  
And Function

scholarly journals Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Yu ◽  
Yan-Chuan Shi ◽  
Fan Ping ◽  
Wei Li ◽  
Hua-Bing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Loss ◽  
Bone Quality ◽  
Normal Glucose Tolerance ◽  
Bone Fragility ◽  
Protective Effects ◽  
Mineral Density ◽  
Normal Glucose ◽  
Glucagon Like Peptide 1

BackgroundThe mechanisms of bone fragility in type 1 diabetes (T1D) are not fully understood. Whether glucagon-like peptide-1 receptor (GLP-1R) agonists could improve bone quality in T1D context also remains elusive.AimsWe aimed to explore the possible mechanisms of bone loss in T1D and clarify whether liraglutide has effects on bone quality of T1D mice using transcriptomics.MethodsFemale streptozotocin-induced diabetic C57BL/6J mice were randomly divided into four groups and received the following treatments daily for 8 weeks: saline as controls, insulin, liraglutide, and liraglutide combined with insulin. These groups were also compared with non-STZ-treated normal glucose tolerance (NGT) group. Trunk blood and bone tissues were collected for analysis. Three tibia from each of the NGT, saline-treated, and liraglutide-treated groups were randomly selected for transcriptomics.ResultsCompared with NGT mice, saline-treated T1D mice manifested markedly hyperglycemia and weight loss, and micro-CT revealed significantly lower bone mineral density (BMD) and deficient microarchitectures in tibias. Eight weeks of treatment with liraglutide alone or combined with insulin rescued the decreased BMD and partly corrected the compromised trabecular microarchitectures. Transcriptomics analysis showed there were 789 differentially expressed genes mainly mapped to osteoclastogenesis and inflammation pathways. The RT-qPCR verified that the gene expression of Trem2, Nfatc1, Trap, and Ctsk were significantly increased in the tibia of T1D compared with those in the NGT group. Liraglutide treatment alone or combined with insulin could effectively suppress osteoclastogenesis by downregulating the gene expression of Trem2, Nfatc1, Ctsk, and Trap.ConclusionsTaken together, increased osteoclastogenesis with upregulated expression of Trem2 played an important role in bone loss of T1D mice. Liraglutide provided protective effects on bone loss in T1D mice by suppressing osteoclastogenesis.

scholarly journals Patterns of Immune Infiltration in Endometriosis and Their Relationship to r-AFS Stages

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiyu Zhong ◽  
Fan Yang ◽  
Xiaochuan Chen ◽  
Jinbo Li ◽  
Cailing Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cells ◽  
Plasma Cells ◽  
Immune Cell ◽  
M2 Macrophages ◽  
Expression Data ◽  
Gene Expression Microarray Data ◽  
And Function ◽  
Ovarian Endometriomas ◽  
Activation Status

Background: Endometriosis (EMS) is an estrogen-dependent disease in which endometrial glands and stroma arise outside the uterus. Current studies have suggested that the number and function of immune cells are abnormal in the abdominal fluid and ectopic lesion tissues of patients with EMS. The developed CIBERSORT method allows immune cell profiling by the deconvolution of gene expression microarray data.Methods: By applying CIBERSORT, we assessed the relative proportions of immune cells in 68 normal endometrial tissues (NO), 112 eutopic endometrial tissues (EU) and 24 ectopic endometrial tissues (EC). The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. We obtained associations between the immune cell environment and EMS r-AFS stages. Macrophages were evaluated by immunohistochemistry (IHC) in 60 patients with ovarian endometriomas.Results: Total natural killer (NK) cells were significantly decreased in EC, while plasma cells and resting CD4 memory T cells were increased in EC. Total macrophages in EC were significantly increased compared to those of EU and NO, and M2 macrophages were the primary macrophages in EC. Compared to those of EC from patients with r-AFS stage I ~ II, M2 macrophages in EC from patients with stage III ~ IV were significantly increased. IHC experiments showed that total macrophages were increased in EC, with M2 macrophages being the primary subtype.Conclusions: Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition in EMS.

scholarly journals Autophagy-Associated IL-15 Production Is Involved in the Pathogenesis of Leprosy Type 1 Reaction

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2215
Author(s):  
Bruno Jorge de Andrade Silva ◽  
Tamiris Lameira Bittencourt ◽  
Thyago Leal-Calvo ◽  
Mayara Abud Mendes ◽  
Rhana Berto da Silva Prata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Skin Cells ◽  
Expression Of Genes ◽  
Autophagy Induction ◽  
Autophagy Pathway ◽  
Ifn Γ ◽  
And Function

Leprosy reactional episodes are acute inflammatory events that may occur during the clinical course of the disease. Type 1 reaction (T1R) is associated with an increase in neural damage, and the understanding of the molecular pathways related to T1R onset is pivotal for the development of strategies that may effectively control the reaction. Interferon-gamma (IFN-γ) is a key cytokine associated with T1R onset and is also associated with autophagy induction. Here, we evaluated the modulation of the autophagy pathway in Mycobacterium leprae-stimulated cells in the presence or absence of IFN-γ. We observed that IFN-γ treatment promoted autophagy activation and increased the expression of genes related to the formation of phagosomes, autophagy regulation and function, or lysosomal pathways in M. leprae-stimulated cells. IFN-γ increased interleukin (IL)-15 secretion in M. leprae-stimulated THP-1 cells in a process associated with autophagy activation. We also observed higher IL15 gene expression in multibacillary (MB) patients who later developed T1R during clinical follow-up when compared to MB patients who did not develop the episode. By overlapping gene expression patterns, we observed 13 common elements shared between T1R skin lesion cells and THP-1 cells stimulated with both M. leprae and IFN-γ. Among these genes, the autophagy regulator Translocated Promoter Region, Nuclear Basket Protein (TPR) was significantly increased in T1R cells when compared with non-reactional MB cells. Overall, our results indicate that IFN-γ may induce a TPR-mediated autophagy transcriptional program in M. leprae-stimulated cells similar to that observed in skin cells during T1R by a pathway that involves IL-15 production, suggesting the involvement of this cytokine in the pathogenesis of T1R.

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