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Fulltext Pharmacologically antagonizing the CXCR4-CXCL12 chemokine pathway with AMD3100 inhibits sunlight-induced skin cancer

Sarchio SNE, Scolyer RA, Beaugie C, McDonald D, Marsh-Wakefield F, Halliday GM, et al.

J Invest Dermatol, 2014 Apr;134(4):1091-1100.
PMID: 24226205 DOI: 10.1038/jid.2013.424

One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.

Matched MeSH terms: Mast Cells/metabolism; Mast Cells/radiation effects
Mucosal responses of brown-marbled grouper Epinephelus fuscoguttatus (Forsskål, 1775) following intraperitoneal infection with Vibrio harveyi

Chieng CCY, Daud HM, Yusoff FM, Thompson KD, Abdullah M

J Fish Dis, 2020 Oct;43(10):1249-1258.
PMID: 32830331 DOI: 10.1111/jfd.13222

Groupers are popular aquaculture species in South-East Asia, but their cultivation is affected by infectious disease outbreaks. Mucosa-associated lymphoid tissues provide a first-line defence against pathogens; however, few studies are available relating to cellular or proteomic responses of mucosal immunity in grouper. Skin, gill and intestine were sampled from brown-marbled grouper Epinephelus fuscoguttatus (Forsskål, 1775) at 4 and 96 hr post-infection (hpi) and 7 days post-infection (dpi) following intraperitoneal infection with Vibrio harveyi, and stained with haematoxylin/eosin and Alcian Blue/periodic acid-Schiff. Skin mucus was analysed by 2D-gel electrophoresis, and proteins modulated by the bacterial infection identified. In the infected fish, significant increases in sacciform cells in skin and increased levels of nucleoside diphosphate kinase in mucus were detected at 4 hpi. At 96 hpi, goblet cells containing acidic mucins significantly increased in the intestine, while those containing mixed mucins increased in skin and gills of infected fish. Proteasome subunit alpha type-I and extracellular Cu/Zn superoxide dismutase levels also increased in mucus. Rodlet and mast cells did not appear to respond to the infection. Mucosal tissues of grouper appeared actively involved in response to Vibrio infection. This information may help future research on improving grouper health, production and vaccine development.

Matched MeSH terms: Mast Cells
Clinacanthus nutans aqueous leaves extract exerts anti-allergic activity in preclinical anaphylactic models via alternative IgG pathway

Kow ASF, Khoo LW, Tan JW, Abas F, Lee MT, Israf DA, et al.

J Ethnopharmacol, 2023 Mar 01;303:116003.
PMID: 36464074 DOI: 10.1016/j.jep.2022.116003

ETHNOPHARMACOLOGICAL RELEVANCE: Allergy is mediated by the crosslinking of immunoglobulins (Ig) -E or -G to their respective receptors, which degranulates mast cells, macrophages, basophils, or neutrophils, releasing allergy-causing mediators. The removal of these mediators such as histamine, platelet-activating factor (PAF) and interleukins (ILs) released by effector cells will alleviate allergy. Clinacanthus nutans (C. nutans), an herbal plant in Southeast Asia, is used traditionally to treat skin rash, an allergic symptom. Previously, we have reported that C. nutans aqueous leaves extract (CNAE) was able to suppress the release of β-hexosaminidase and histamine but not interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α) in the IgE-induced mast cell degranulation model at 5 mg/mL and above. We also found that CNAE could protect rats against ovalbumin-challenged active systemic anaphylaxis (OVA-ASA) through the downregulation and upregulation of certain metabolites using proton nuclear magnetic resonance (1H-NMR) metabolomics approach.
AIM OF THE STUDY: As allergy could be mediated by both IgE and IgG, we further evaluated the anti-allergy potential of CNAE in both in vitro model of IgG-induced macrophage activation and in vivo anaphylaxis models to further dissect the mechanism of action underlying the anti-allergic properties of CNAE.
MATERIAL & METHODS: The anti-allergy potential of CNAE was evaluated in in vivo anaphylaxis models of ovalbumin-challenged active systemic anaphylaxis (OVA-ASA) and IgE-challenged passive systemic anaphylaxis (PSA) using Sprague Dawley rats as well as IgG-challenged passive systemic anaphylaxis (IgG-PSA) using C57BL/6 mice. Meanwhile, in vitro model of IgG-induced macrophage activation model was performed using IC-21 macrophages. The release of soluble mediators from both IgE and IgG-mediated pathways were measured using enzyme-linked immunosorbent assay (ELISA). The signaling molecules targeted by CNAE were identified by performing Western blot.
RESULTS: IgG, platelet-activating factor (PAF) and IL-6 was suppressed by CNAE in OVA-ASA, but not IgE. In addition, CNAE significantly suppressed PAF and IL-6 in IgG-PSA but did not suppress histamine, IL-4 and leukotrienes C4 (LTC4) in IgE-PSA. CNAE also inhibited IL-6 and TNF-α by inhibiting the phosphorylation of ERK1/2 in the IgG-induced macrophage activation model.
CONCLUSION: Overall, our findings supported that CNAE exerts its anti-allergic properties by suppressing the IgG pathway and its mediators by inhibiting ERK1/2 phosphorylation, thus providing scientific evidence supporting its traditional use in managing allergy.

Matched MeSH terms: Mast Cells

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