Department of Microbiology and Immunology, Virginia Commonwealth University, Box 980678, Richmond, VA 23298-0678, USA.
Department of Biochemistry, Virginia Commonwealth University, Box 980614, Richmond, VA 23298-0614, USA.
Cell Immunol. 2020 Oct;356:104134. doi: 10.1016/j.cellimm.2020.104134. Epub 2020 May 30.
Mast cells, well established effectors in allergic disease, can be activated by numerous stimuli. We previously found that the Fyn-Stat5B pathway is critical for FcεRI-stimulated mast cell function. Because IgG receptors employ similar signaling pathways, we investigated Fyn-Stat5B function downstream of FcγR. We report that FcγR elicits Fyn-dependent Stat5B tyrosine phosphorylation in mast cells. As we previously found for Fyn kinase, Stat5B is indispensable for IgG-mediated mast cell cytokine expression and secretion. However, Stat5B KO macrophages responded normally to FcγR signaling, indicating a lineage-restricted role for Stat5B. This was consistent in vivo, since passive FcγR activation induced anaphylaxis in a macrophage-dominated response even when Stat5B was deleted. We further investigated this lineage restriction using the K/BxN model of inflammatory arthritis. This model exhibits a rapid and transient mast cell-dependent joint inflammation followed days later by a macrophage- and neutrophil-dependent response. Consistent with our hypothesis, Fyn or Stat5B deficiency did not protect mice from late joint swelling, but greatly reduced the early mast cell-dependent response. This was associated with decreased joint and plasma histamine. We conclude that Fyn-Stat5B is a linage-restricted pathway critical for IgG-mediated mast cell responses.
肥大细胞是过敏疾病中成熟的效应细胞，可以被多种刺激激活。我们之前发现 Fyn-Stat5B 途径对 FcεRI 刺激的肥大细胞功能至关重要。由于 IgG 受体采用类似的信号通路，我们研究了 FcγR 下游的 Fyn-Stat5B 功能。我们报告 FcγR 在肥大细胞中引发 Fyn 依赖性 Stat5B 酪氨酸磷酸化。正如我们之前对 Fyn 激酶的发现，Stat5B 对于 IgG 介导的肥大细胞细胞因子表达和分泌是必不可少的。然而，Stat5B KO 巨噬细胞对 FcγR 信号的反应正常，表明 Stat5B 在谱系上受到限制。这在体内是一致的，因为即使 Stat5B 缺失，被动 FcγR 激活也会诱导以巨噬细胞为主的过敏反应。我们使用炎症性关节炎的 K/BxN 模型进一步研究了这种谱系限制。该模型表现出快速和短暂的肥大细胞依赖性关节炎症，随后几天出现巨噬细胞和中性粒细胞依赖性反应。与我们的假设一致，Fyn 或 Stat5B 的缺失不能保护小鼠免受晚期关节肿胀，但大大减少了早期肥大细胞依赖性反应。这与关节和血浆组织胺的减少有关。我们得出结论，Fyn-Stat5B 是一种谱系受限的途径，对于 IgG 介导的肥大细胞反应至关重要。
