Disease Risk-Associated Genetic Variants in STAT1 and STAT4 Function in a Complementary Manner to Increase Pattern-Recognition Receptor-Induced Outcomes in Human Macrophages.
Disease Risk-Associated Genetic Variants in STAT1 and STAT4 Function in a Complementary Manner to Increase Pattern-Recognition Receptor-Induced Outcomes in Human Macrophages.
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DOI：
10.4049/jimmunol.1901112
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发表时间：
2020-09-01
期刊：
影响因子：
--
通讯作者：
Abraham C
中科院分区：
文献类型：
--
作者：
Hedl M;Sun R;Abraham C
STAT蛋白可以调节促炎性和抗炎性细胞因子信号。因此，确定调节特定STAT表达的结果对于确定其作为治疗靶点的潜力以及确定STAT基因中免疫介导的疾病变异对疾病发病机制的作用至关重要。STAT1/STAT4区域的遗传变异与多种免疫介导的疾病相关，包括炎症性肠病（IBD）。这些疾病的特征是响应模式识别受体（PRR）刺激的细胞因子分泌失调。我们发现常见的ibd相关rs1517352 C风险等位基因增加了人单核细胞源性巨噬细胞（MDMs）中STAT1和STAT4的表达。因此，我们假设STAT1/STAT4变体可能以互补和合作的方式调节prr启动的应答，因为自分泌/旁分泌细胞因子在调节prr启动的信号传导中起着重要作用。STAT1和STAT4是PRR和活菌诱导的多种细胞因子分泌所必需的。这些结果特别依赖于prr启动的自分泌/旁分泌il -12诱导的STAT4激活以产生IFN-γ，然后自分泌IFN-γ通过STAT1信号传导。STAT1和STAT4还促进肠髓细胞中细菌诱导的细胞因子和MDMs中prr增强的抗菌途径。重要的是，来自rs1517352 C IBD风险等位基因携带者的MDMs显示，TLR4-、IFN-γ -和il -12诱导的STAT1和STAT4磷酸化和细胞因子分泌增加，TLR4增强的抗菌途径增加。综上所述，STAT1和STAT4的表达由一个共享的遗传区域共同调节，STAT1/STAT4免疫疾病相关变异体调节IFN-γ -和il -12相关的结果，进而调节prr诱导的结果，强调这些基因合作调节与疾病发病机制相关的途径。
STAT proteins can regulate both pro- and anti-inflammatory cytokine signaling. Therefore, identifying consequences of modulating expression of a given STAT is ultimately critical for determining its potential as a therapeutic target and for defining the mechanisms through which immune-mediated disease variants in STAT genes contribute to disease pathogenesis. Genetic variants in the STAT1/STAT4 region are associated with multiple immune-mediated diseases, including inflammatory bowel disease (IBD). These diseases are characterized by dysregulated cytokine secretion in response to pattern-recognition receptor (PRR) stimulation. We found that the common IBD-associated rs1517352 C risk allele increased both STAT1 and STAT4 expression in human monocyte-derived macrophages (MDMs). We therefore hypothesized that the STAT1/STAT4 variant might regulate PRR-initiated responses in a complementary and cooperative manner because of the important role of autocrine/paracrine cytokines in modulating PRR-initiated signaling. STAT1 and STAT4 were required for PRR- and live bacterial-induced secretion of multiple cytokines. These outcomes were particularly dependent on PRR-initiated autocrine/paracrine IL-12–induced STAT4 activation to generate IFN-γ, with autocrine IFN-γ then signaling through STAT1. STAT1 and STAT4 also promoted bacterial-induced cytokines in intestinal myeloid cells and PRR-enhanced antimicrobial pathways in MDMs. Importantly, MDMs from rs1517352 C IBD risk allele carriers demonstrated increased TLR4-, IFN-γ– and IL-12–induced STAT1 and STAT4 phosphorylation and cytokine secretion and increased TLR4-enhanced antimicrobial pathways. Taken together, STAT1 and STAT4 expression is coregulated by a shared genetic region, and STAT1/STAT4-immune disease–associated variants modulate IFN-γ– and IL-12–associated outcomes, and in turn, PRR-induced outcomes, highlighting that these genes cooperate to regulate pathways relevant to disease pathogenesis.
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DOI：
10.4049/jimmunol.1600845
发表时间：
2016-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hedl M;Proctor DD;Abraham C
通讯作者：
Abraham C
影响因子：
27.4
作者：
Abelson AK;Delgado-Vega AM;Kozyrev SV;Sánchez E;Velázquez-Cruz R;Eriksson N;Wojcik J;Linga Reddy MV;Lima G;D'Alfonso S;Migliaresi S;Baca V;Orozco L;Witte T;Ortego-Centeno N;AADEA group;Abderrahim H;Pons-Estel BA;Gutiérrez C;Suárez A;González-Escribano MF;Martin J;Alarcón-Riquelme ME
通讯作者：
Alarcón-Riquelme ME
影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
29.4
作者：
Hedl M;Abraham C
通讯作者：
Abraham C
影响因子：
10.5
作者：
O'Shea JJ;Schwartz DM;Villarino AV;Gadina M;McInnes IB;Laurence A
通讯作者：
Laurence A