Inflammation is a key factor in the pathogenesis of dry eye disease (DED). We aimed to investigate the role of microRNA-146a (miR-146a) in regulating corneal inflammation in a mouse model of benzalkonium chloride (BAC)-induced dry eye and the TNF-α-induced NF-κB signaling pathway in human corneal epithelial cells (HCECs). A mouse model of dry eye was established by administering with BAC to BALB/c mice, and the expression of TNF-α, IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) in the corneas of dry eye model mice was significantly increased; this was accompanied by the upregulation of miR-146a and activation of the NF-κB pathway. In vitro, TNF-α induced miR-146a expression in HCECs, while the NF-κB inhibitor SC-514 reduced the expression of miR-146a. Overexpression of miR-146a decreased the expression of IRAK1 and TRAF6, which have been identified as targets of miR-146a. Furthermore, overexpression of miR-146a suppressed NF-κB p65 translocation from the cytoplasm to the nucleus. Moreover, overexpression of miR-146a attenuated the TNF-α-induced expression of IL-6, IL-8, COX2 and intercellular adhesion molecule 1 (ICAM1), while inhibition of miR-146a exerted the opposite effect. Our results suggest that miR-146a mediates the inflammatory response in DED. MiR-146a negatively regulates inflammation in HCECs through the IRAK1/TRAF6/NF-κB pathway, and this may serve as a potential therapeutic approach for the treatment of DED.

01 Jul 2022·BiomaterialsQ1 · ENGINEERING & TECHNOLOGY

Robust tolerogenic dendritic cells via push/pull pairing of toll-like-receptor agonists and immunomodulators reduces EAE

Q1 · ENGINEERING & TECHNOLOGY

Article

Author: Esser-Kahn, Aaron ; Deak, Peter ; Knight, Hannah Riley

A failure of central immune tolerance driven by autoantigen specific T regulatory (Treg) cells is a major cause of many autoimmune diseases. Restoration of proper autoantigen Treg specific response holds promise as a highly effective, long-term therapy for a wide variety of autoimmune diseases. Generating autoantigen specific Tregs remains a challenge due to the non-specific nature of most tolerizing agents and the complexities of generating Tregs in vivo. Here we show a new push/pull method for inducing antigen-specific Treg tolerance via induction of tolerogenic dendritic cells (tolDCs). We identified a combination of three tolerogenic drugs, dexamethasone, simvastatin and SC-514, which when used in combination with toll-like-receptor (TLR) agonists induces an active tolDC phenotype. When the tolerogenic combination was packaged into a liposome with a model antigen such as ovalbumin (OVA), these tolDCs induce differentiation of OVA specific Tregs both ex vivo and in vivo. We examined the tolerizing potential of the combination in an experimental autoimmune encephalomyelitis (EAE) disease model. Given the antigen specificity of this technique, this paper presents an attractive preclinical autoimmune therapy.

01 Dec 2021·CARTILAGEQ3 · MEDICINE

Effect of Inflammatory Signaling on Human Articular Chondrocyte Hypertrophy: Potential Involvement of Tissue Repair Macrophages

Q3 · MEDICINE

Article

Author: Bastiaansen-Jenniskens, Yvonne M. ; Ferrao Blanco, Mauricio N. ; Narcisi, Roberto ; Pitsillides, Andrew A. ; van Osch, Gerjo J.V.M. ; Chambers, Mark G.

Objective In osteoarthritis, chondrocytes tend to acquire a hypertrophic phenotype, which contributes to the modification of the extracellular matrix, resulting in permanent cartilage changes. In mouse chondrocytes, pro-inflammatory macrophages and pro-inflammatory cytokines have been shown to stimulate hypertrophy via the activation of the nuclear factor kappa B (NF-κB) pathway. Whether or not this also occurs in human chondrocytes remains unclear. We therefore aimed to investigate whether hypertrophy-like responses in human cartilage are driven mainly by intrinsic inflammatory signaling or shaped by specific macrophage populations. Design Human articular chondrocytes were cultured with pro-inflammatory cytokines or medium conditioned by defined macrophage subsets. Furthermore, the effect of inhibition of NF-κB-dependent gene expression was evaluated using the NF-κB inhibitor SC-514. Hypertrophy was assessed by measuring the transcription level of alkaline phosphatase ( ALPL), type X collagen ( COL10A1), Indian hedgehog ( IHH), and runt-related transcription factor 2 ( RUNX2). Results The expression of hypertrophic genes was not promoted in human chondrocytes by pro-inflammatory cytokines neither pro-inflammatory M(IFNγ + TNFα) macrophages. Inhibition of the NF-κB-dependent gene expression did not affect human articular chondrocyte hypertrophy. However, tissue repair M(IL4) macrophages induced hypertrophy by promoting the expression of COL10A1, RUNX2, and IHH. Conclusion Intrinsic inflammatory signaling activation is not involved in the hypertrophic shift observed in human articular chondrocytes cultured in vitro. However, tissue repair macrophages may contribute to the onset of this detrimental phenotype in human osteoarthritic cartilage, given the effect observed in our experimental models.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	US	Pfizer Inc.	-

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