JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages.
JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages.
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DOI：
10.4049/jimmunol.1600845
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发表时间：
2016-11-01
期刊：
影响因子：
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通讯作者：
Abraham C
中科院分区：
文献类型：
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作者：
Hedl M;Proctor DD;Abraham C
JAK2基因变异与炎症性肠病(IBD)有关，JAK抑制剂正在评估针对免疫介导性疾病的治疗，包括IBD。由于JAK途径介导的细胞因子调节因细胞类型和刺激条件的不同而不同，我们研究了JAK信号和IBD相关JAK2变体如何调节人类髓系细胞中不同的急性和慢性微生物产品暴露结果，分别与最初进入和持续肠道组织停留的条件一致。携带IBD危险基因rs10758669 CC的对照组和溃疡性结肠炎患者的巨噬细胞显示，与AA携带者相比，JAK2的表达和NOD2诱导的JAK2磷酸化增加。有趣的是，JAK2表达和信号传递的阈值决定了模式识别受体(PRR)诱导的结果；当抗炎细胞因子随着JAK2表达的降低而逐渐减少时，促炎细胞因子在低于某一JAK2表达阈值时从减少分泌转为增加分泌。低JAK2表达的rs10758669 AA巨噬细胞高于这个阈值；因此，PRR诱导的促炎和抗炎细胞因子都减少了。然而，相对于CC风险携带者rs10758669，AA携带者巨噬细胞在较低的治疗使用JAK抑制剂剂量时转向增加NOD2诱导的促炎细胞因子。重要的是，JAK抑制剂增加了慢性PRR刺激后外周巨噬细胞和暴露于肠道病原体后的人肠道髓系细胞分泌的促炎细胞因子。从机制上讲，髓系细胞对自分泌/旁分泌IL-10、IL-4、IL-22和胸腺基质淋巴生成素的反应和分泌减少调节了这些JAK依赖的结果。综上所述，JAK信号阈值决定了PRR诱导的促炎和抗炎细胞因子在髓系细胞中是否相互调节；考虑JAK2基因和特定细胞类型的靶向可能会改善JAK靶向治疗免疫介导性疾病。
JAK2 genetic variants are associated with inflammatory bowel disease (IBD) and JAK inhibitors are being evaluated for therapy targeting immune-mediated diseases, including IBD. As JAK pathway-mediated cytokine regulation varies across cell types and stimulation conditions, we examined how JAK signaling and IBD-associated JAK2 variants regulate distinct acute and chronic microbial product exposure outcomes in human myeloid cells, consistent with the conditions of initial entry and ongoing intestinal tissue residence, respectively. Macrophages from controls and ulcerative colitis patients carrying the IBD-risk rs10758669 CC genotype showed increased JAK2 expression and NOD2-induced JAK2 phosphorylation relative to AA carriers. Interestingly, the threshold of JAK2 expression and signaling determined pattern-recognition receptor (PRR)-induced outcomes; while anti-inflammatory cytokines progressively decreased with lower JAK2 expression, pro-inflammatory cytokines switched from decreased to increased secretion below a certain JAK2 expression threshold. Low JAK2-expressing rs10758669 AA macrophages were above this threshold; consequently, both PRR-induced pro- and anti-inflammatory cytokines were decreased. However, relative to rs10758669 CC risk-carriers, AA carrier macrophages switched to increased NOD2-induced pro-inflammatory cytokines at lower therapeutically-used JAK inhibitor doses. Importantly, JAK inhibitors increased pro-inflammatory cytokines secreted by peripheral macrophages following chronic PRR stimulation and by human intestinal myeloid cells following exposure to intestinal pathogens. Mechanistically, the decreased response to and secretion of autocrine/paracrine IL-10, IL-4, IL-22 and thymic stromal lymphopoietin regulated these JAK-dependent outcomes in myeloid cells. Taken together, JAK signaling threshold determines whether PRR-induced pro- and anti-inflammatory cytokines are reciprocally regulated in myeloid cells; consideration of JAK2 genotype and targeting of specific cell types might improve JAK-targeted therapy in immune-mediated diseases.