Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).Peer reviewe

Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).Peer reviewe

Congestive heart failure : more common as well as an important cardiovascular outcome: reply

Non peer reviewe

Leg Ulcers Treated with Topical Tacrolimus in Patients with Rheumatoid Arthritis

Non peer reviewe

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown. We, therefore, investigated the role of hBD2–histamine crosstalk signaling in promoting OLP pathology. Biopsies from OLP and oral tongue squamous cell carcinoma (OTSCC) patients, and healthy controls were used. Two OTSCC cell lines and normal human oral keratinocytes (HOKs) were used. HBD-2 and other targets were mapped by immunostaining and analyzed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinically derived and in vitro samples, respectively. H4R was challenged with the specific agonist HST-10 and inverse agonist ST-1007. HBD-2 was highly induced in OLP lesions. In contrast, hBD2 expression was attenuated in OTSCC tissues, while very low levels of hBD-2 messenger RNA (mRNA) were observed in OTSCC cells. Together with tumor necrosis factor-α (TNF-α), histamine upregulated hBD-2 mRNA expression in HOKs. Activation of H4R seems to modulate the expression of epithelial hBD-2. These findings suggest the involvement of hBD-2 in the pathogenesis of OLP and may, thus, be harnessed for therapeutic interventions in OLP

Activation of NLRP3 Inflammasome in the Skin of Patients with Systemic and Cutaneous Lupus Erythematosus

NLRP3 inflammasome is suggested to contribute to the complex pathogenesis of systemic lupus erythematosus, but its role in cutaneous lupus erythematosus has not been addressed. This study investigated the expression of NLRP3 inflammasome components and levels of type I interferons in the skin of 20 patients with cutaneous lupus erythematosus. Expression of NLRP1/3, adaptor protein ASC (apoptosis-associated speck-like protein), caspase-1, interferon-alpha (IFN-alpha), myxovirus resistance protein (MxA), and interferon-induced proteins 1 and 2 (IFIT 1/2) in the skin was assessed using reverse transcription quantitative real-time PCR (RT-qPCR), western blotting and immunohistochemistry. Serum interferon-a protein levels from 12 patients were measured using digital enzyme-linked immunoassay (ELISA). Interleukin-1 beta expression was significantly upregulated in the lesional skin of patients with cutaneous lupus erythematosus compared with their uninvolved skin. However, NLRP1/3, ASC and caspase-1 were not significantly upregulated compared with the skin of control persons. IFN-alpha and IFN-induced proteins MxA and IFIT1/2 were strongly expressed in cutaneous lupus erythematosus skin. Variability in the expression of NLRP3 inflammasome components among patients suggests heterogeneity of pathological pathways in cutaneous lupus erythematosus.Peer reviewe

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown. We, therefore, investigated the role of hBD2–histamine crosstalk signaling in promoting OLP pathology. Biopsies from OLP and oral tongue squamous cell carcinoma (OTSCC) patients, and healthy controls were used. Two OTSCC cell lines and normal human oral keratinocytes (HOKs) were used. HBD-2 and other targets were mapped by immunostaining and analyzed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinically derived and in vitro samples, respectively. H4R was challenged with the specific agonist HST-10 and inverse agonist ST-1007. HBD-2 was highly induced in OLP lesions. In contrast, hBD2 expression was attenuated in OTSCC tissues, while very low levels of hBD-2 messenger RNA (mRNA) were observed in OTSCC cells. Together with tumor necrosis factor-α (TNF-α), histamine upregulated hBD-2 mRNA expression in HOKs. Activation of H4R seems to modulate the expression of epithelial hBD-2. These findings suggest the involvement of hBD-2 in the pathogenesis of OLP and may, thus, be harnessed for therapeutic interventions in OLP

Severity and progression rate of periodontitis are associated with an increased risk of hypertension of patients attending the university clinic

Peer reviewe

IL-17A and TNF synergistically drive expression of proinflammatory mediators in synovial fibroblasts via I kappa B zeta-dependent induction of ELF3

Objective IL-17A and TNF act in synergy to induce proinflammatory mediators in synovial fibroblasts thus contributing to diseases associated with chronic arthritis. Many of these factors are regulated by transcription factor E74-like factor-3 (ELF3). Therefore, we sought to investigate ELF3 as a downstream target of IL-17A and TNF signalling and to characterize its role in the molecular mechanism of synergy between IL-17A and TNF. Methods Regulation of ELF3 expression by IL-17A and TNF was studied in synovial fibroblasts of RA and OA patients and RA synovial explants. Signalling leading to ELF3 mRNA induction and the impact of ELF3 on the response to IL-17A and TNF were studied using siRNA, transient overexpression and signalling inhibitors in synovial fibroblasts and HEK293 cells. Results ELF3 was marginally affected by IL-17A or TNF alone, but their combination resulted in high and sustained expression. ELF3 expression was regulated by the nuclear factor-kappa B (NF-kappa B) pathway and CCAAT/enhancer-binding protein beta (C/EBP beta), but its induction required synthesis of the NF-kappa B co-factor I kappa B (inhibitor of NF-kappa B) zeta. siRNA-mediated depletion of ELF3 attenuated the induction of cytokines and matrix metalloproteinases by the combination of IL-17A and TNF. Overexpression of ELF3 or I kappa B zeta showed synergistic effect with TNF in upregulating expression of chemokine (C-C motif) ligand 8 (CCL8), and depletion of ELF3 abrogated CCL8 mRNA induction by the combination of I kappa B zeta overexpression and TNF. Conclusion Altogether, our results establish ELF3 as an important mediator of the synergistic effect of IL-17A and TNF in synovial fibroblasts. The findings provide novel information of the pathogenic mechanisms of IL-17A in chronic arthritis and implicate ELF3 as a potential therapeutic target.Peer reviewe

Behcet disease (BD) and BD-like clinical phenotypes : NF-kappa B pathway in mucosal ulcerating diseases

Behcet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namelyHLA-B*51,ERAP1,IL-10,IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNF alpha, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-kappa B activation (egTNFAIP3,NFKB1,OTULIN,RELA,IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-kappa B pathway suggesting new elements in the elusive BD etiopathogenesis.Peer reviewe