Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease

P055 CXCL13 as biomarker for histological involvement in sjogren's syndrome

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CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Use of orthodontic methods in the treatment of dental luxations: A scoping review

(1) Background: Treating dental luxation injuries is challenging for the clinician. Dental luxations account for 18–33% of injuries to permanent teeth and can be addressed using different therapeutic approaches. The present work was conducted with two aims: (i) to evaluate, through a scoping review, current knowledge of the orthodontic methods (repositioning and stabilization splinting) that can be used at the time of the trauma, and (ii) to investigate the frequency and type of pulp consequences arising after these traumatic injuries. (2) Methods: The literature search was conducted in the period June 2020–December 2020 using the PubMed/MEDLINE, SCOPUS and Web of Science databases. The research questions were formulated according to the PICO (Population, Intervention, Comparison, Outcomes) method and considered the following aspects: type of luxation injury and stage of root development; use of orthodontic repositioning and splinting techniques; frequency and type of pulp consequences; and compliance of treatments with international guidelines. (3) Results: The initial screening of the databases, using the selected search keywords, yielded a total of 587 articles, just 8 fully met the inclusion criteria. Closer analysis of these 8 publications revealed that they would not produce clear meta-analytical data. This made it necessary to limit the data collected to the following six items: number and type of injuries, initial therapeutic intervention, duration of follow-up, number, and type of different pulp consequences. (4) Conclusions: While orthodontic techniques are commonly used to treat dental intrusions, in the case of extrusive and lateral luxation injuries, they are less frequently used and the orthodontic approach is generally confined to the stabilization phase. Among the various possible pulp consequences, many authors consider only pulp canal obliteration (PCO) and pulp necrosis (PN), often tending to overlook physiological healing (pulp survival) and the possible development of PN after PCO. There is therefore a clear need for new, high-quality clinical studies of this topic based on systematic and standardized data collection

Multiple modes of action mediate the therapeutic effect of IVIg in experimental epidermolysis bullosa acquisita

Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG (IVIg) in patients with autoimmunity are well-established treatments. Data on the mode of action of IVIg are, however, controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG treatment in murine autoantibody-induced skin inflammation, namely, epidermolysis bullosa acquisita (EBA). EBA is caused by antibodies directed against type VII collagen (COL7) and is mediated by complement activation, release of reactive oxygen species, and proteases by myeloid cells. In murine experimental EBA the disease can be induced by injection of anti-COL7 IgG. Here, we substantiate that treatment with high-dose IgG improves clinical disease manifestation. Mechanistically, high-dose IgG reduced the amount of anti-COL7 in skin and sera, which is indicative for an FcRn-dependent mode-of-action. Furthermore, in a non-receptor-mediated fashion, high-dose IgG showed antioxidative properties by scavenging extracellular reactive oxygen species. High-dose IgG also impaired complement activation and served as substrate for proteases, both key events during EBA pathogenesis. Collectively, the non-receptor-mediated anti-inflammatory properties of high-dose IgG may explain the therapeutic benefit of IVIg treatment in skin autoimmunity

I polifenoli del foraggio di sulla per il miglioramento del benessere degli animali da latte e della qualità dei formaggi (DISOLASULLA)

Il progetto coinvolge per il triennio 2021-2023 due gruppi di ricerca afferenti a UNIPA e UNIPI nell’intento di valorizzare le potenzialità del foraggio di sulla (Sulla coronaria (L.) Medik.) nell’alimentazione dei ruminanti, proponendone la disidratazione per la costituzione di scorte. L’ipotesi è che la disidratazione consenta, in alternativa alla fienagione, di preservare le proprietà della sulla legate alla sua componente polifenolica, costituita principalmente da tannini condensati (TC). Ingeriti con la dieta, i TC esercitano attività antiossidante, migliorando la termo-tolleranza e lo stato immunitario degli animali, riducono la metanogenesi e le emissioni di metano nell’ambiente, limitano la degradabilità delle proteine alimentari e ne migliorano l’utilizzazione digestiva, da cui l’aumento di caseina nel latte e minori escrezioni di azoto nell’ambiente, e proteggono gli acidi grassi polinsaturi dalla bioidrogenazione ruminale, aumentandone il trasferimento nei prodotti. Su tali basi, il progetto mira a verificare se l’utilizzazione della sulla disidratata nella dieta delle pecore da latte comporti, al pari della sulla verde, effetti positivi su benessere e produttività degli animali, qualità tecnologica del latte, proprietà microbiologiche e nutrizionali dei prodotti caseari e sostenibilità ambientale. Le attività sperimentali sono volte alla produzione di latte e formaggi da pecore di razza Valle del Belìce in Sicilia e Massese in Toscana, alimentate con diete a base di sulla fresca, affienata o disidratata. Sugli animali si valutano i consumi alimentari, la digeribilità della dieta, la produzione di latte, lo stato immunitario e ossidativo in base a indicatori ematici, e l’ambiente biochimico e microbiologico del rumine mediante analisi del liquido ruminale. Sul latte sono determinati i parametri fisico-chimici che ne definiscono la qualità tecnologica e nutrizionale, mentre sui formaggi vengono rilevati i componenti che possono avere impatto positivo sulla salute dei consumatori, come acidi grassi polinsaturi, vitamine, polifenoli e capacità antiossidante. Gli effetti dei TC sono valutati anche sulle dinamiche microbiche rilevabili durante la fermentazione del latte e la maturazione del formaggio. Inoltre, le indagini sui formaggi prendono in esame la stabilità ossidativa, il profilo aromatico e le proprietà sensoriali valutate mediante test di tipo descrittivo e discriminante. L’impatto del sistema di produzione in termini di emissioni di azoto e metano nell’ambiente viene stimato in base ai parametri ruminali e di efficienza alimentare. I risultati ottenuti possono contribuire allo sviluppo della tecnica di disidratazione e pellettatura del foraggio di sulla e alla valorizzazione sul mercato di prodotti caseari “disolasulla”, in linea con le esigenze dei consumatori attenti ai sistemi di allevamento degli animali per quanto riguarda il tipo e la qualità degli alimenti somministrati, il loro benessere e la sostenibilità ambientale

Autophagy occurs in lymphocytes infiltrating Sjögren’s syndrome minor salivary glands and correlates with histological severity of salivary gland lesions

Backgrounds: The organization of minor salivary glands (MSG) infiltrates, in patients with Sjögren’s syndrome (SS), associates with disease severity and progression. Aberrant regulation of lymphocyte autophagy is involved in autoimmunity, and in previous work, we provided the first evidence of upregulated autophagy in CD4+ T cells infiltrating SS MSG. The aim of this study was to further explore autophagy in SS infiltrating and circulating lymphocytes and to investigate its role in disease histopathological progression. Methods: After collection of 20 SS MSG, the presence of lymphocyte aggregates (foci) and the formation of germinal center (GC)-like structures were observed by H&E and confirmed by immunohistochemistry. The expression of autophagy-related genes, Atg5 and MAP1LC3A, was detected by RT-PCR on microdissected salivary gland tissue and control tonsils. In MSG and tonsils, autophagic lymphocytes were identified by the detection of the autophagosome protein LC3B visualized as LC3 puncta staining by immunofluorescence. Peripheral blood autophagy was assessed by flow cytometry in SS and healthy controls (HC). Results: Real-time PCR demonstrated higher expression in the autophagy genes Atg5 and MAP1LC3A in MSG GCs as compared to both small foci (p = 0.0075, p = 0.0002) and GCs from tonsils (p = 0.0001, p = 0.0037). In MSG, LC3 puncta staining was detectable on both CD3+ and CD20+ lymphocytes; in tonsils, LC3 puncta was almost undetectable on all lymphocytes. Compared to HC (n = 20), flow cytometry did not reveal any increase of autophagy in SS circulating lymphocytes (n = 30). Conclusions: In SS MSG, lymphocytes’ autophagy is a feature of infiltrating T and B cells and is associated with histological severity. Interestingly, in MSG aberrant regulation of autophagy is detectable in GC-like structures possibly indicating its involvement in the development and persistence of the autoimmune process within the lesions