Loss of protein tyrosine phosphatase non-receptor type 2 reduces IL-4-driven alternative macrophage activation.
Loss of protein tyrosine phosphatase non-receptor type 2 reduces IL-4-driven alternative macrophage activation.
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DOI：
10.1038/s41385-021-00441-3
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发表时间：
2022-01
影响因子：
8
通讯作者：
McCole DF
中科院分区：
文献类型：
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作者：
Spalinger MR;Crawford M;Bobardt SD;Li J;Sayoc-Becerra A;Santos AN;Shawki A;Chatterjee P;Nair MG;McCole DF
巨噬细胞是先天性免疫细胞的一个异质性群体，通常分为两个主要亚群：经典激活的、通常具有促炎作用（M1）的巨噬细胞，其介导宿主防御；以及选择性激活的、诱导耐受（M2）的巨噬细胞，其发挥内稳态和组织再生功能。巨噬细胞功能/分化紊乱会导致免疫激活不足、过度，或者无法诱导针对病原体的有效保护性免疫反应。蛋白酪氨酸磷酸酶非受体2型（PTPN2）的功能缺失变异与慢性炎症性疾病有关，但巨噬细胞内在的PTPN2缺失所产生的影响仍知之甚少。在此我们报道，PTPN2缺陷型巨噬细胞无法获得选择性激活/M2表型。这是白细胞介素 - 6（IL - 6）受体表达降低以及无法在IL - 6刺激下诱导白细胞介素 - 4（IL - 4）受体的结果，从而导致无法对关键的M2诱导细胞因子IL - 4作出反应。最终，无法对IL - 6和IL - 4作出充分反应导致体外M1巨噬细胞标志物表达水平升高，以及在体内感染巴西日圆线虫时肺部炎症加剧。这些结果表明，PTPN2缺失干扰了巨噬细胞对炎症刺激作出充分反应的能力，并可能解释了PTPN2功能缺失携带者患炎症性疾病易感性增加的原因。
Macrophages are a heterogeneous population of innate immune cells that are often divided into two major subsets: classically activated, typically pro-inflammatory (M1) macrophages that mediate host defense, and alternatively activated, tolerance-inducing (M2) macrophages that exert homeostatic and tissue-regenerative functions. Disturbed macrophage function/differentiation results either in inadequate, excessive immune activation or in a failure to induce efficient protective immune responses against pathogens. Loss-of-function variants in protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with chronic inflammatory disorders, but the effect of macrophage-intrinsic PTPN2 loss is still poorly understood. Here we report that PTPN2-deficient macrophages fail to acquire an alternatively activated/M2 phenotype. This was the consequence of reduced IL-6 receptor expression and a failure to induce IL-4 receptor in response to IL-6, resulting in an inability to respond to the key M2-inducing cytokine IL-4. Ultimately, failure to adequately respond to IL-6 and IL-4 resulted in increased levels of M1 macrophage marker expression in vitro and exacerbated lung inflammation upon infection with Nippostrongylus brasiliensis in vivo. These results demonstrate that PTPN2 loss interferes with the ability of macrophages to adequately respond to inflammatory stimuli and might explain the increased susceptibility of PTPN2 loss-of-function carriers to developing inflammatory diseases.
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82.9
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