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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PURPOSE OF REVIEWThis review provides an update on the new interleukin-1 (IL-1) cytokine family members in inflammatory diseases with focus on recent findings concerning the family members IL-36, ...IL-37, and IL-38 and their different expression patterns.
RECENT FINDINGSThe IL-1 cytokines are known to be involved in many different inflammatory and autoimmune diseases. The latest IL-1 family members, IL-36, IL-37, and IL-38 have been shown to be differently regulated during course of disease. Studies of patients suffering from inflammatory diseases revealed that those cytokines are upregulated in the serum as well as in inflamed tissue. Both, epithelial cells and infiltrating peripheral mononuclear blood cells serve as source of the cytokines IL-36, IL-37, and IL-38 triggering different outcomes. These results could be confirmed in different mouse models and in-vitro and ex-vivo studies.
SUMMARYIL-36, IL-37, and IL-38 are involved in the pathogenesis of the inflammatory diseases psoriasis, rheumatoid arthritis, gout, systemic lupus erythematosus as well as Crohnʼs disease. Thereby IL-36 acts proinflammatory triggering further inflammatory mediators. In contrast, IL-37 and IL-38 are upregulated to counteract. Understanding the imbalance of the IL-1 family is crucial for future therapeutics.
Objective
On the way to a modern digital healthcare system, Germany becomes a driver of innovation by integrating digital health applications (Digitale Gesundheitsanwendungen (DiGAs)) into standard ...care. Although all insured persons of the statutory health insurance are eligible for a registered DiGA, utilisation has been rather restrained so far. There seems to be a lack of acceptance among healthcare providers. The aim of this study is to analyse the acceptance of DiGAs in non-pharmacological therapies.
Methods
A total of 150 therapists from the fields of physical therapy, occupational therapy, and speech-language pathology participated in an online survey. The questionnaire captured knowledge, intention to use, opinions on advantages and disadvantages of DiGA usage as well as general technology acceptance and commitment.
Results
About 36% of the therapists knew DiGAs, while about 64% had not yet heard of these offers. In addition, 87% of the respondents can imagine integrating DiGAs into their treatment or were already doing so at the time of the survey. Potentials for using DiGAs are seen especially in the quality improvement of therapy, in the increase of the sustainability of the therapy and in promotion of patients’ health literacy. The therapists stated barriers in the lack of technical infrastructure and in the patients’ insufficient digital health literacy.
Conclusion
The results indicate the potential for DiGAs to be further implemented in non-pharmacological therapies. The facilitators and barriers identified allow recommendations to be derived for relevant stakeholders.
Eosinophils are involved in tissue homeostasis. Herein, we unveiled eosinophils as important regulators of bone homeostasis. Eosinophils are localized in proximity to bone-resorbing osteoclasts in ...the bone marrow. The absence of eosinophils in ΔdblGATA mice results in lower bone mass under steady-state conditions and amplified bone loss upon sex hormone deprivation and inflammatory arthritis. Conversely, increased numbers of eosinophils in IL-5 transgenic mice enhance bone mass under steady-state conditions and protect from hormone- and inflammation- mediated bone loss. Eosinophils strongly inhibit the differentiation and demineralization activity of osteoclasts and lead to profound changes in the transcriptional profile of osteoclasts. This osteoclast-suppressive effect of eosinophils is based on the release of eosinophil peroxidase causing impaired reactive oxygen species and mitogen-activated protein kinase induction in osteoclast precursors. In humans, the number and the activity of eosinophils correlates with bone mass in healthy participants and rheumatoid arthritis patients. Taken together, experimental and human data indicate a regulatory function of eosinophils on bone.
Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived ...immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model.
A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0-7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA).
A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization.
BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Interleukin (IL)-36α is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), ...its ligand IL-36α and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36α induces MAP-kinase and NFκB signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines.
To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36α signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36α was tested in murine and human osteoclast assays.
Diseased mice showed an increased expression of IL-36R and IL-36α in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays.
Thus we conclude that IL-36α does not affect the development of inflammatory arthritis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1β, IL-6, RANKL, ...MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP
osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages,
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., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts
the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
Autoantibodies to double‐stranded (ds) DNA represent a serological hallmark of systemic lupus erythematosus (SLE) and may critically contribute to the pathogenesis of lupus nephritis. Self‐reactive ...antibodies might be partially produced by long‐lived plasma cells (PCs), which mainly reside within the bone marrow and spleen. In contrast to short‐lived PCs, long‐lived PCs are extremely resistant to therapy and may sustain refractory disease courses. Recently, antibody‐secreting cells were found within the inflamed kidneys of New Zealand black/white (NZB/W) F1 lupus mice as well as of patients with SLE. To analyze the longevity of the IgG‐producing cells present in nephritic kidneys of NZB/W F1 mice we performed in vivo BrdU‐labeling. We identified a higher frequency of long‐lived than short‐lived renal PCs, indicating that survival niches for long‐lived PCs also exist within inflamed kidneys. Using ELISPOT assays, we found that on average 31% of renal IgG‐producing cells reacted with dsDNA and 24% with nucleolin. Moreover, the frequencies of IgG‐secreting cells specific for the autoantigens dsDNA and nucleolin were higher in the kidneys compared with those in the spleen and bone marrow.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is ...involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation.
PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined.
Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (p
= 0.001; p
= 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (
= 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (
= 0.007), but not in its subepithelial layers (
= 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years.
Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.
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