Model Of Inflammatory Arthritis Research Articles

Fishroesomes show intrinsic anti-inflammatory bioactivity and ability as celecoxib carriers in vivo.

According to the World Health Organization (WHO), chronic inflammatory-related diseases represent the greatest threat to human health. Indeed, failure in the resolution of inflammation leads to serious pathological conditions, such as cardiovascular diseases, arthritis, cancer, diabetes, autoimmune diseases, and neurodegenerative disorders that are often associated with extremely high human suffering and societal and economic burdens. Despite the number and efficacy of available therapeutic agents have been increased, the serious side effects associated with some of them often create a very high risk/benefit ratio for patients. Therefore, herein, a drug delivery system was engineered to overcome important drawbacks of conventional therapies and to have a synergistic action with the incorporated drug. Indeed, it will have an added beneficial role in controlling inflammation. For that, sardine (Sardina pilchardus) roe was used as the lipidic source to produce bioactive liposomes, namely fishroesomes. These spherical vesicles with ≈326 nm in size and a significant negative surface charge (≈-31 mV) were able to encapsulate and control the release of the anti-inflammatory drug celecoxib. Moreover, fishroesomes were cytocompatible for different cell types (chondrocytes and macrophages), at concentrations in which they present anti-inflammatory properties. Importantly, fishroesomes were more effective in reducing pro-inflammatory mediators than the free drug. We also demonstrated that a single intra-articular injection of the fishroesomes encapsulating or not celecoxib in an experimental rat model of inflammatory arthritis was safe and more effective in controlling the pain and reducing the synovial inflammation compared to the free drug. Notably, as the celecoxib concentration in the sardine roe-derived liposomes was less than half of the amount of free drug, this study demonstrates the value of fishroesomes in counteracting inflammation. Therefore, the developed formulations may be considered a promising therapeutic option for inflammatory conditions.

Regulation of neutrophil associated RNASET2 expression in rheumatoid arthritis

Neutrophils (PMNs) are key players of innate immune responses through the release of cytoplasmic granule content and the formation of neutrophil extracellular traps (NETs). RNASET2 is an acidic ribonuclease, recently proposed as an alarmin signal associated with inflammatory responses. Here we show that, along the neutrophil maturation cascade, RNASET2 is expressed in segmented and mature PMNs. In human PMNs, RNASET2 colocalized with primary and tertiary granules and was found to be associated with NETs following PMA or Nigericin stimulation. Similarly, activation of PMNs by soluble immune complexes, a hallmark of several autoimmune diseases, also induced RNASET2-associated NETs. Genome-wide association studies recently identified RNASET2 among a cluster of genes associated with increased susceptibility to develop autoimmune diseases, including rheumatoid arthritis (RA). RNASET2 was found expressed by PMNs and macrophages infiltrating inflamed joints in a murine model of RA (K/BxN Serum-Transfer-Induced Arthritis, STIA), by immunostaining. Similar results were found in synovial biopsies of RA patients with active disease. In addition, we demonstrate that RNASET2 circulating levels correlated with the onset and the severity of disease in two mouse models of inflammatory arthritis, STIA and CIA (Collagen-Induced Arthritis) and in serum of RA patients. These results show that PMNs are an important source of RNASET2 and that its circulating levels are associated with RA development suggesting a role for RNASET2 in the pathogenesis of immune-mediated diseases.

Androgen Exhibits a Protective Role Against Focal Erosions in Murine TNF-induced Inflammatory Arthritis.

Rheumatoid arthritis (RA) is characterized by erosive pathology associated with joint inflammation and a sexual dimorphism with increased prevalence in females. Here, we aim to determine whether androgen is protective against inflammatory-erosive disease in TNF-transgenic (TNF-Tg) mice. Wild-type (WT) and TNF-Tg male mice underwent sham (WT, n = 3; TNF-Tg, n = 7) or orchiectomy (WT, n = 3; TNF-Tg, n = 7) surgery at 1 month old to remove androgen production confirmed by serum testosterone concentration. Cohorts of orchiectomized TNF-Tg males were treated with either 5ɑ-dihydrotestosterone (.025 mg/day) (n = 3) or placebo (n = 3) via subcutaneous pellet insertion. Weekly clinical measures, along with mid-hindpaw bone volumes and ankle histology at 3 months old were evaluated for all groups. Orchiectomies in TNF-Tg males significantly decreased serum testosterone (P < .05), weight gain (P < .001), and mid-hindpaw bone volumes (P < .05) in comparison to sham TNF-Tg mice. The cuboid bone also had increased synovitis by histology with the loss of androgen (P < .05). Treatment of orchiectomized TNF-Tg males with 5ɑ-dihydrotestosterone protected against the changes in weight gain (P < .01) and bone erosion (P < .05) associated with decreased osteoclast number in the cuboid (P < .01). In the TNF-Tg model of chronic inflammatory arthritis, androgen is protective in erosive disease. The loss of endogenous androgen significantly accelerated the progression of inflammatory-erosive arthritis in male TNF-Tg mice to a similar severity as age-matched female mice. In addition, treatment with exogenous androgen prevented this observed bone loss in orchiectomized TNF-Tg males. Overall, androgen delays and limits bone erosion even in the presence of active inflammation and future studies are warranted to elucidate the associated mechanisms.

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. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

Engineering Peptide‐Oligonucleotide Nano‐Conjugates via Click Reaction as Self‐Delivery System for Gene Therapy of Inflammatory Arthritis

AbstractIntracellular oligonucleotide delivery possesses unparalleled potential for precise regulation of pathogenic gene expression and alteration of cell destiny. However, limited by its feeble resistance against humoral environment, hindered intracellular transportation, and lysosomal phagocytosis, oligonucleotide therapy remains a formidable challenge. The discovery of cationic peptides has provided innovative insights for the effective delivery of oligonucleotides, yet the stable, efficient, and convenient assembly of peptides and oligonucleotides remains an elusive goal, referred to as the “Holy Grail” challenge in the field. Addressing this challenge, it has pioneered the development of a straightforward and highly efficient engineering carrier‐free covalent peptide‐oligonucleotide nano‐conjugates (PONs) through a mild click reaction. Notably, this PONs can realize self‐assemble into nanoparticles under amphiphilic electrostatic interactions, which exhibits significant RNase resistance and surprisingly effective intracellular oligonucleotide delivery as well as lysosomal escape. Based on this strategy, a PONs named CPP‐(DOPA)6‐miRNA‐223 is synthesized, which demonstrates rapid and effective cellular uptake, swift lysosomal escape in macrophage, remarkable accumulation in inflammatory regions and excellent therapeutic effect in an inflammatory arthritis model. Therefore, this work may provide a breakthrough for the clinical application of all oligonucleotide delivery therapies and expanding the applications in gene therapy.

Fibroblast-like synoviocytes orchestrate daily rhythmic inflammation in arthritis.

Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time-of-day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. The deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.

14-3-3ζ suppresses RANKL signaling by destabilizing TRAF6

Macrophages are essential regulators of inflammation and bone loss. RANKL, a pro-inflammatory cytokine, is responsible for macrophage differentiation to osteoclasts and bone loss. We recently showed that 14-3-3ζ-knockout (YwhazKO) rats exhibit increased bone loss in the inflammatory arthritis model. 14-3-3ζ is a cytosolic adaptor protein that actively participates in many signaling transductions. However, the role of 14-3-3ζ in RANKL signaling or bone remodeling is unknown. We investigated how 14-3-3ζ affects osteoclast activity by evaluating its role in RANKL signaling. We utilized 14-3-3ζ-deficient primary bone marrow-derived macrophages (BMDMs) obtained from wildtype (Wt) and YwhazKO animals, and RAW cells generated using CRISPR-Cas9. Our results showed that 14-3-3ζ-deficient macrophages, upon RANKL stimulation, have bigger and stronger TRAP-positive multinucleated cells and increased bone resorption activity. The presence of 14-3-3ζ suppressed RANKL-induced MAPK and AKT phosphorylation, transcription factors (NFATC1 and p65) nuclear translocation, and subsequently, gene induction (Rank, Acp5, and Ctsk). Mechanistically, 14-3-3ζ interacts with TRAF6, an essential component of the RANKL receptor complex. Upon RANKL stimulation, 14-3-3ζ-TRAF6 interaction was increased, while RANK-TRAF6 interaction was decreased. Importantly, 14-3-3ζ supported TRAF6 ubiquitination and degradation by the proteasomal pathway, thus dampening the downstream RANKL signaling. Together, we show that 14-3-3ζ regulates TRAF6 levels to suppress inflammatory RANKL signaling and osteoclast activity. To the best of our knowledge, this is the first report on 14-3-3ζ regulation of RANKL signaling and osteoclast activation.

Dietary omega-3 fatty acids modulate the production of platelet-derived microvesicles in an in vivo inflammatory arthritis model.

The aim of this study was to investigate the effects of different ω-3 polyunsaturated fatty acid (PUFA) enriched diets, including a novel renewable plant source of ω-3 fatty acids (Buglossoides arvensis), on the development and progression of rheumatoid arthritis (RA). RA was induced in mice consuming experimental diets using the K/BxN model. The experimental diets consisted of either a western control diet (control), diets containing B. arvensis oil or fish oil. The effects of the diets on platelets, platelet microvesicles (PMVs), and inflammatory markers such as clinical index, ankle thickness and cytokine/chemokine release were measured. While ω-3 PUFA-enriched diets did not prevent the development of arthritis in the K/BxN model, a significant decrease in ankle swelling was observed compared to the control group. Platelets isolated from mice consuming either low content of B. arvensis oil or fish oil diets exhibited significantly decreased PMVs production compared to mice consuming the control diet. Our study provides insight into the contribution of ω-3 PUFA supplementation in modulating the pro-inflammatory phenotype of platelets in RA pathology. Furthermore, our study suggests that low concentrations of dietary B. arvensis oil may have similar anti-inflammatory potential seen with dietary fish oil supplementation.

A novel mouse model of silicosis and silica-induced inflammatory arthritis.

A novel mouse model of silicosis and silica-induced inflammatory arthritis.

C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice.

The biosynthesis of C-reactive protein (CRP) in the liver is increased in inflammatory diseases including rheumatoid arthritis. Previously published data suggest a protective function of CRP in arthritis; however, the mechanism of action of CRP remains undefined. The aim of this study was to evaluate the effects of human CRP on the development of collagen-induced arthritis (CIA) in mice which is an animal model of autoimmune inflammatory arthritis. Two CRP species were employed: wild-type CRP which binds to aggregated IgG at acidic pH and a CRP mutant which binds to aggregated IgG at physiological pH. Ten CRP injections were given on alternate days during the development of CIA. Both wild-type and mutant CRP reduced the incidence of CIA, that is, reduced the number of mice developing CIA; however, CRP did not affect the severity of the disease in arthritic mice. The serum levels of IL-17, IL-6, TNF-α, IL-10, IL-2 and IL-1β were measured: both wild-type and mutant CRP decreased the level of IL-17 and IL-6 but not of TNF-α, IL-10, IL-2 and IL-1β. These data suggest that CRP recognizes and binds to immune complexes, although it was not clear whether CRP functioned in its native pentameric or in its structurally altered pentameric form in the CIA model. Consequently, ligand-complexed CRP, through an as-yet undefined mechanism, directly or indirectly, inhibits the production of IL-17 and eventually protects against the initiation of the development of arthritis. The data also suggest that IL-17, not TNF-α, is critical for the development of autoimmune inflammatory arthritis.

Locomotor activity as an effective measure of the severity of inflammatory arthritis in a mouse model.

Mouse models are valuable in preclinical studies of inflammatory arthritis. However, current methods for measuring disease severity or responses to treatment are not optimal. In this study a smart cage system using multiple sensors to measure locomotor activity was evaluated in the K/BxN serum transfer model of inflammatory arthritis. Arthritis was induced in C57BL/6 mice with injections of K/BxN serum. Clinical index and ankle thickness were measured for 14 days. Locomotor activity was measured in smart cages for 23 h periods on Days 0, 7, and 13. The same measurements were taken in mice consuming diets supplemented or not with fish oil to evaluate a preventative treatment. Initiation, peak and resolution phases of disease could be measured with the smart cages. Locomotor activity including speed, travel distance, number of active movements and rear movements were all significantly lower on Days 7-8 of illness (peak) compared to Days 0 and 13-14 (resolution) (one-way repeated measures analyses, p<0.05). The clinical index and ankle thickness measurements did not capture differences between dietary groups. Significantly increased activity was measured in most of the locomotor parameters in the fish oil group compared to the control mice at both Days 8 and 14 (2-way repeated measures ANOVA, p<0.05). The measurement of locomotor activity provided a more detailed evaluation of the impact of inflammatory arthritis on animal well-being and mobility than that provided by measuring clinical index and ankle thickness, and could be a valuable tool in preclinical studies of inflammatory arthritis.

ABCD of IA: A multi-scale agent-based model of T cell activation in inflammatory arthritis.

Biomaterial-based agents have been demonstrated to regulate the function of immune cells in models of autoimmunity. However, the complexity of the kinetics of immune cell activation can present a challenge in optimizing the dose and frequency of administration. Here, we report a model of autoreactive T cell activation, which are key drivers in autoimmune inflammatory joint disease. The model is termed a multi-scale Agent-Based, Cell-Driven model of Inflammatory Arthritis (ABCD of IA). Using kinetic rate equations and statistical theory, ABCD of IA simulated the activation and presentation of autoantigens by dendritic cells, interactions with cognate T cells and subsequent T cell proliferation in the lymph node and IA-affected joints. The results, validated with in vivo data from the T cell driven SKG mouse model, showed that T cell proliferation strongly correlated with the T cell receptor (TCR) affinity distribution (TCR-ad), with a clear transition state from homeostasis to an inflammatory state. T cell proliferation was strongly dependent on the amount of antigen in antigenic stimulus event (ASE) at low concentrations. On the other hand, inflammation driven by Th17-inducing cytokine mediated T cell phenotype commitment was influenced by the initial level of Th17-inducing cytokines independent of the amount of arthritogenic antigen. The introduction of inhibitory artificial antigen presenting cells (iaAPCs), which locally suppress T cell activation, reduced T cell proliferation in a dose-dependent manner. The findings in this work set up a framework based on theory and modeling to simulate personalized therapeutic strategies in IA.

Bona fide dendritic cells are pivotal precursors for osteoclasts

ObjectivesOsteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined.MethodsCD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated...

Noninvasive PET Detection of CD69-Positive Immune Cells Before Signs of Clinical Disease in Inflammatory Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory joint disease, and early diagnosis is key for effective disease management. CD69 is one of the earliest cell surface markers seen at the surface of activated immune cells, and CD69 is upregulated in synovial tissue in patients with active RA. In this study, we evaluated the performance of a CD69-targeting PET agent, [68Ga]Ga-DOTA-ZCAM241, for early disease detection in a model of inflammatory arthritis. Methods: A model of inflammatory arthritis was induced by transferring splenocytes from KRN T-cell receptor transgenic B6 mice into T-cell-deficient I-Ag7 major histocompatibility complex class II-expressing recipient mice. The mice were examined longitudinally by [68Ga]Ga-DOTA-ZCAM241 PET/CT before and 3, 7, and 12 d after induction of arthritis. Disease progression was monitored by clinical parameters, including measuring body weight and scoring the swelling of the paws. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the paws was analyzed and expressed as SUVmean Tissue biopsy samples were analyzed for CD69 expression by flow cytometry or immunostaining for a histologic correlate. A second group of mice was examined by a nonbinding, size-matched Affibody molecule as the control. Results: Clinical symptoms appeared 5-7 d after induction of arthritis. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the joints was negligible at baseline but increased gradually after disease induction. An elevated PET signal was found on day 3, before the appearance of clinical symptoms. The uptake of [68Ga]Ga-DOTA-ZCAM241 correlated with the clinical score and disease severity. The presence of CD69-positive cells in the joints and lymph nodes was confirmed by flow cytometry and immunostaining. The uptake of the nonbinding tracer that was the negative control also increased gradually with disease progression, although to a lesser extent than with [68Ga]Ga-DOTA-ZCAM241 Conclusion: The uptake of [68Ga]Ga-DOTA-ZCAM241 in the inflamed joints preceded the clinical symptoms in the KRN T-cell transfer model of inflammatory arthritis, in accordance with immunostaining for CD69. [68Ga]Ga-DOTA-ZCAM241 is thus a promising PET imaging marker of activated immune cells in tissue during RA onset.

Geraniol Suppresses Oxidative Stress, Inflammation, and Interstitial Collagenase to Protect against Inflammatory Arthritis.

Geraniol (GER) is a plant-derived acyclic isoprenoid monoterpene that has displayed anti-inflammatory effects in numerous in vivo and in vitro models. This study was therefore designed to evaluate the antiarthritic potential of GER in complete Freund's adjuvant (CFA)-induced inflammatory arthritis (IA) model in rats. IA was induced by intraplantar injection of CFA (0.1 mL), and a week after CFA administration, rats were treated with various doses of methotrexate (MTX; 1 mg/kg) or GER (25, 50, and 100 mg/kg). Treatments were given on every alternate day, and animals were sacrificed on the 35th day. Paw volume, histopathological, hematological, radiographic, and qPCR analyses were performed to analyze the severity of the disease. GER significantly reduced paw edema after 35 days of treatment, and these results were comparable to the MTX-treated group. GER-treated animals displayed a perfect joint structure with minimal inflammation and no signs of cartilage or bone damage. Moreover, GER restored red blood cell and hemoglobin levels, normalized erythrocyte sedimentation rate, platelet, and c-reactive protein values, and also attenuated the levels of rheumatoid factor. RT-qPCR analysis demonstrated that GER decreased mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta. GER also down-regulated the transcript levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1, prostaglandin D2 synthase, and interstitial collagenase (MMP-1). Molecular docking of GER with COX-2, TNF-α, and MMP-1 also revealed that the antiarthritic effects of GER could be due to its direct interactions with these mediators. Based on our findings, it is conceivable that the antiarthritic effects of GER could be attributed to downregulation of pro-inflammatory mediators and protease like MMP-1.

Epigenetic and transcriptional regulation of CCL17 production by glucocorticoids in arthritis

Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis. Here, we provide molecular evidence that GCs can suppress GM-CSF-mediated upregulation of IRF4 and CCL17 expression via downregulating JMJD3 expression and activity. In mouse models of inflammatory arthritis, GC treatment inhibited CCL17 expression and ameliorated arthritic pain-like behavior and disease. Significantly, GC treatment of RA patient peripheral blood mononuclear cells exvivo resulted in decreased CCL17 production. This delineated pathway potentially provides new therapeutic options for the treatment of many inflammatory conditions, where GCs are used as an anti-inflammatory drug but without the associated adverse side effects.

Refractory inflammatory arthritis definition and model generated through patient and multi-disciplinary professional modified Delphi process.

Various definitions have been proposed for Refractory Disease in people with Rheumatoid Arthritis; however, none were generated for Polyarticular Juvenile Idiopathic Arthritis or involving adult and paediatric multidisciplinary healthcare professionals and patients. The study aim is to redefine Refractory Disease, using Delphi methodology. Three rounds of surveys (one nominal group and two online (2019-2020)) to achieve consensus using a predetermined cut-off were conducted voting on: a) name, b) treatment and inflammation, c) symptoms and impact domains, and d) rating of individual components within domains. Theoretical application of the definition was conducted through a scoping exercise. Votes were collected across three rounds from Patients, Researchers and nine multi-disciplinary healthcare professional groups (n = 106). Refractory Inflammatory Arthritis was the most popular name. Regarding treatment and inflammation, these were voted to be kept broad rather than specifying numbers/cut-offs. From 10 domains identified to capture symptoms and disease impact, six domains reached consensus for inclusion: 1) Disease Activity, 2) Joint Involvement, 3) Pain, 4) Fatigue, 5) Functioning and Quality of Life, and 6) Disease-Modifying Anti-Rheumatic Drug Experiences. Within these domains, 18 components, from an initial pool (n = 73), were identified as related and important to capture multi-faceted presentation of Refractory Inflammatory Arthritis, specifically in Rheumatoid Arthritis and Polyarticular Juvenile Idiopathic Arthritis. Feasibility of the revised definition was established (2022-2023) with good utility as was applied to 82% of datasets (n = 61) incorporating 20 outcome measures, with two further measures added to increase its utility and coverage of Pain and Fatigue. Refractory Inflammatory Arthritis has been found to be broader than not achieving low disease activity, with wider biopsychosocial components and factors incorporating Persistent Inflammation or Symptoms identified as important. This definition needs further refinement to assess utility as a classification tool to identify patients with unmet needs.

Receptor tyrosine kinases Tyro3, Axl, and Mertk differentially contribute to antibody-induced arthritis

Tyro3, Axl, and Mertk (abbreviated TAMs) comprise a family of homologous type 1 receptor tyrosine kinases (RTKs) that have been implicated as inhibitory receptors that dampen inflammation, but their roles in the pathogenesis of rheumatoid arthritis remains understudied. Here, to investigate TAMs in an inflammatory arthritis model, antibody-induced arthritis in single TAM-deficient mice (Tyro3- KO, Axl-KO, Mertk-KO) was induced by K/BxN serum injection. Subsequently, joint inflammation and cytokine levels, as well as the expression of Fcγ Rs and complement receptors were assessed in WT and TAM-deficient mice. Compared with littermate control mice, Axl−/− and Mertk−/− mice developed more severe antibody-induced arthritis, while in contrast, Tyro3−/− mice showed diminished joint inflammation. Concomitantly, the levels of cytokines in joints of Axl−/− and Mertk−/− mice were also significantly increased, while cytokines in the Tyro3−/− joint tissues were decreased. At the molecular and cellular level, TAMs showed distinct expression patterns, whereby monocytes expressed Axl and Mertk, but no Tyro3, while neutrophils expressed Axl and Tyro3 but little Mertk. Moreover, expression of Fcγ receptors and C5aR showed different patterns with TAMs expression, whereby FcγRIV was higher in monocytes of Axl−/− and Mertk−/− mice compared to wild-type mice, while Tyro3−/− neutrophils showed lower expression levels of FcγRI, FcγRIII and FcγRIV. Finally, expression of C5aR was increased in Mertk−/− monocytes, and was decreased in Tyro3−/− neutrophils. These data indicate that Axl, Mertk and Tyro3 have distinct functions in antibody-induced arthritis, due in part to the differential regulation of cytokines production, as well as expression of FcγRs and C5aR.1eHRq_qjGV2iQGKkb-YYk-Video

MRNA vaccine against fibroblast activation protein ameliorates murine models of inflammatory arthritis.

Synovial fibroblasts in patients with rheumatoid arthritis (RA) contribute substantially to the perpetuation of synovitis and invasion to cartilage and bone, and are potential therapeutic targets. Fibroblast activation protein (FAP) is highly expressed by RA synovial fibroblasts and the expression is relatively specific. We tested whether FAP can serve as a molecular target to modulate synovial fibroblasts for therapy in experimental arthritis. mRNA encoding consensus FAP (cFAP) was encapsulated in lipid nanoparticles (LNP) and was injected intramuscularly as vaccine prior to induction of collagen-induced arthritis (CIA) and collagen antibody induced arthritis (CAIA) in mice. Development of CIA and CAIA was assessed clinically and by histology. cFAP mRNA-LNP vaccine provoked immune response to cFAP and mouse FAP (mFAP); prevented onset of CIA in 40% of mice and significantly reduced the severity of arthritis. In CAIA, cFAP mRNA-LNP did not prevent onset of arthritis but significantly reduced the severity of arthritis. cFAP mRNA-LNP vaccine was able to provoke immune response to mFAP and suppress inflammatory arthritis.

Galectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease

Musculoskeletal chronic pain is prevalent in individuals with Alzheimer’s disease (AD); however, it remains largely untreated in these patients, raising the possibility that pain mechanisms are perturbed. Here, we utilise the TASTPM transgenic mouse model of AD with the K/BxN serum transfer model of inflammatory arthritis. We show that in male and female WT mice, inflammatory allodynia is associated with a distinct spinal cord microglial response characterised by TLR4-driven transcriptional profile and upregulation of P2Y12. Dorsal horn nociceptive afferent terminals release the TLR4 ligand galectin-3 (Gal-3), and intrathecal injection of a Gal-3 inhibitor attenuates allodynia. In contrast, TASTPM mice show reduced inflammatory allodynia, which is not affected by the Gal-3 inhibitor and correlates with the emergence of a P2Y12− TLR4− microglia subset in the dorsal horn. We suggest that sensory neuron-derived Gal-3 promotes allodynia through the TLR4-regulated release of pro-nociceptive mediators by microglia, a process that is defective in TASTPM due to the absence of TLR4 in a microglia subset.