S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation

Abstract

BackgroundThe calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.ObjectiveTo address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.MethodsBone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.ResultsFollowing OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.ConclusionS100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.

Human placental extract suppresses mast cell activation and induces mast cell apoptosis

“…For some of the PCA assays, Evans blue was obviated and ear tissues were sectioned and analyzed with toluidine blue staining for revealing mast cell morphology as previously described [ 23 ]. Or alternatively, the ear sections were processed for histamine analysis as previously described [ 24 ].…”

FcγR‐dependent apoptosis regulates tissue persistence of mucosal and connective tissue mast cells

“…BM derived‐cultured mast cells (BMMC) were obtained as previously described [46]. Essentially, BM cells were maintained at 37°C in 5% CO 2 in RPMI 1640 medium containing 4 mM L‐glutamine supplemented with 10% FBS, and 50 μM 2‐ME, 1 mM sodium pyruvate, 0.1 mM MEM nonessential AAs, as well as penicillin and streptomycin.…”

New Mechanistic Advances in FcεRI-Mast Cell–Mediated Allergic Signaling

“…Orai-1 inhibition can reduce the calcium influx, leading to weakened mediator release [73], while Orai-2 deletion can open CRAC channels, and increase Ca 2+ concentrations in mast cells, leading to enhanced anaphylaxis [74]. In addition, the intracellular Ca 2+ concentrations are also regulated by the two-pore channels that are engaged in inducing endolysosomal calcium uptake and ER calcium filling [75], and by the calcium-binding protein S100A4 whose depletion is associated with decreased serum allergen-specific IgE and pro-inflammatory cytokines [76].…”