Molecular Blocking of CD23 Supports Its Role in the Pathogenesis of Arthritis

BACKGROUND: CD23 is a differentiation/activation antigen expressed by a variety of hematopoietic and epithelial cells. It can also be detected in soluble forms in biological fluids. Initially known as the low-affinity receptor for immunoglobulin E (Fc epsilonRII), CD23 displays various other physiologic ligands such as CD21, CD11b/c, CD47-vitronectin, and mannose-containing proteins. CD23 mediates numerous immune responses by enhancing IgE-specific antigen presentation, regulating IgE synthesis, influencing cell differentiation and growth of both B- and T-cells. CD23-crosslinking promotes the secretion of pro-inflammatory mediators from human monocytes/macrophages, eosinophils and epithelial cells. Increased CD23 expression is found in patients during allergic reactions and rheumatoid arthritis while its physiopathologic role in these diseases remains to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We previously generated heptapeptidic countrestructures of human CD23. Based on in vitro studies on healthy and arthritic patients' cells, we showed that CD23-specific peptide addition to human macrophages greatly diminished the transcription of genes encoding inflammatory cytokines. This was also confirmed by significant reduction of mediator levels in cell supernatants. We also show that CD23 peptide decreased IgE-mediated activation of both human and rat CD23(+) macrophages. In vivo studies in rat model of arthritis showed that CD23-blocking peptide ameliorates clinical scores and prevent bone destruction in a dose dependent manner. Ex-vivo analysis of rat macrophages further confirmed the inhibitory effect of peptides on their activation. Taken together our results support the role of CD23 activation and subsequent inflammatory response in arthritis. CONCLUSION: CD23-blocking peptide (p30A) prevents the activation of monocytes/macrophages without cell toxicity. Thus, targeting CD23 by antagonistic peptide decreases inflammatory markers and may have clinical value in the treatment of human arthritis and allergic reactions involving CD23

Pratiques et projets numériques en classe de FLE

Inde

Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis

BACKGROUND: Dietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model. METHODS: RU was added simultaneously to human macrophages during their activation. Cells were then analyzed for inflammation-related gene expression using a specific array, and cell supernatants were collected to measure inflammatory mediators. RU was also injected into adjuvant-induced arthritic rats, and disease progression and body weight were evaluated until 50 days after injection. Sera and peritoneal macrophages were also collected to quantify the RU effect on various inflammatory markers. RESULTS: RU inhibited inflammation-related gene expression in activated human macrophages and the release of nitric oxide, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 from these cells. In a rat model, RU inhibited clinical signs of chronic arthritis, correlating with decreased levels of inflammatory cytokines detected in rat sera and macrophage supernatants. CONCLUSION: Thus, RU may have clinical value in reducing inflammatory manifestations in human arthritis and other inflammatory diseases

CD23 Mediates Antimycobacterial Activity of Human Macrophages▿

Engagement of surface receptors contributes to the antimicrobial activity of human immune cells. We show here that infection of human monocyte-derived macrophages (MDM) with live Mycobacterium avium induced the expression of CD23 on their membrane. Subsequent cross-linking of surface CD23 by appropriate ligands induced a dose-dependent antibacterial activity of MDM and the elimination of most infected cells. The stimulation of inducible nitric oxide synthase-dependent generation of NO from MDM after CD23 activation played a major role during their anti-M. avium activity. CD23 activation also induced tumor necrosis factor alpha (TNF-α) production from MDM. Mycobacteria reduction was partially inhibited by the addition of neutralizing anti-TNF-α antibody to cell cultures without affecting NO levels, which suggested the role of this cytokine for optimal antimicrobial activity. Finally, interleukin-10, a Th2 cytokine known to downregulate CD23 pathway, is shown to decrease NO generation and mycobacteria elimination by macrophages. Therefore, (i) infection with M. avium promotes functional surface CD23 expression on human macrophages and (ii) subsequent signaling of this molecule contributes to the antimicrobial activity of these cells through an NO- and TNF-α-dependent pathway. This study reveals a new human immune response mechanism to counter mycobacterial infection involving CD23 and its related ligands

Rutoside (RU) mediates the inhibition of inflammatory gene transcription in activated human macrophages

Human monocyte-derived macrophages were activated (10 μg/mL CD23-McAb) alone or in the presence of 100 μM RU. After 24 hours of incubation, cellular mRNAs were extracted and analyzed by inflammation-specific macroarray. RU inhibits gene expression by activated human macrophages, with the exception of interleukin (IL)-10. A representative array from two distinct experiments is shown. Inflammatory genes detected on each membrane, in addition to controls. MIF, macrophage migration inhibitory factor; TNF, tumor necrosis factor.<p><b>Copyright information:</b></p><p>Taken from "Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis"</p><p>http://arthritis-research.com/content/10/1/R19</p><p>Arthritis Research & Therapy 2008;10(1):R19-R19.</p><p>Published online 6 Feb 2008</p><p>PMCID:PMC2374451.</p><p></p

Inhibition of inflammatory mediator generation from activated human macrophages

Rutoside (RU) decreased the generation of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 but not IL-10 from activated human macrophages. Inhibition of nitric oxide (NO) generation from human activated macrophages after their incubation with various RU concentrations. RU decreases both intracellular NO (upper panel) and extracellular nitrites (lower panel). Specific inducible nitric oxide synthase inhibitor (L-NIL, 1 mM) was used as control. Results from three different cell preparations ± standard deviation are shown. *value obtained as compared to activated cells. L-NIL, N(6)-(1-iminoethyl)-L-lysine/2HCl.<p><b>Copyright information:</b></p><p>Taken from "Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis"</p><p>http://arthritis-research.com/content/10/1/R19</p><p>Arthritis Research & Therapy 2008;10(1):R19-R19.</p><p>Published online 6 Feb 2008</p><p>PMCID:PMC2374451.</p><p></p

JCI Insight

Loss of melanocytes is the pathological hallmark of vitiligo, a chronic inflammatory skin depigmenting disorder induced by exaggerated immune response, including autoreactive CD8 T cells producing high levels of type 1 cytokines. However, the interplay between this inflammatory response and melanocyte disappearance remains to be fully characterized. Here, we demonstrate that vitiligo skin contains a significant proportion of suprabasal melanocytes, associated with disruption of E-cadherin expression, a major protein involved in melanocyte adhesion. This phenomenon is also observed in lesional psoriatic skin. Importantly, apoptotic melanocytes were mainly observed once cells were detached from the basal layer of the epidermis, suggesting that additional mechanism(s) could be involved in melanocyte loss. The type 1 cytokines IFN-γ and TNF-α induce melanocyte detachment through E-cadherin disruption and the release of its soluble form, partly due to MMP-9. The levels of MMP-9 are increased in the skin and sera of patients with vitiligo, and MMP-9 is produced by keratinocytes in response to IFN-γ and TNF-α. Inhibition of MMP-9 or the JAK/STAT signaling pathway prevents melanocyte detachment in vitro and in vivo. Therefore, stabilization of melanocytes in the basal layer of the epidermis by preventing E-cadherin disruption appears promising for the prevention of depigmentation occurring in vitiligo and during chronic skin inflammation