HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.
HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.
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DOI：
10.1073/pnas.2106017118
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发表时间：
2021-06-29
影响因子：
11.1
通讯作者：
Diamond B
中科院分区：
文献类型：
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作者：
Peng T;Du SY;Son M;Diamond B
临床研究表明，I型干扰素（IFN）产生缺陷或IFN抗体似乎与严重的COVID-19感染相关。在这里，我们表明，促炎细胞因子，但不是I型IFN产生缺氧的人单核细胞。我们发现缺氧抑制I型IFN的产生，但不抑制核因子-κ B依赖性促炎细胞因子的产生。我们证明缺氧诱导因子-1 α是干扰素调节因子的直接转录抑制因子，干扰素调节因子是I型干扰素的转录激活因子。这些发现可能有助于理解和控制严重急性呼吸综合征冠状病毒2型感染导致的IFN产生受损。患有严重COVID-19感染的患者在受影响的组织和血液中表现出低水平的氧气。为了了解COVID-19感染的病理生理学，因此有必要了解缺氧期间的细胞功能。我们研究了缺氧条件下人单核细胞活化的各个方面。HMGB 1是应激细胞释放的一种报警蛋白。在常氧条件下，HMGB 1激活单核细胞中的干扰素调节因子（IRF）5和核因子-κB，分别导致I型干扰素（IFN）和炎症细胞因子（包括肿瘤坏死因子α和白细胞介素1β）的表达。当缺氧单核细胞被HMGB 1激活时，它们产生促炎细胞因子，但不能产生I型IFN。缺氧诱导因子-1 α是由缺氧诱导的，作为IRF 5和IRF 3的直接转录抑制因子发挥作用。由于缺氧是诱导上皮细胞分泌HMGB 1的应激源，因此缺氧建立了有利于单核细胞产生炎性细胞因子而不是IFN的微环境。这些发现对COVID-19的发病机制具有影响。
Clinical studies have shown that defects in type I interferon (IFN) production or antibodies to IFN appear to correlate with severe COVID-19 infection. Here, we demonstrate that proinflammatory cytokines but not type I IFN are produced by hypoxic human monocytes. We show that hypoxia suppresses production of type I IFN but not nuclear factor-κB–dependent proinflammatory cytokines. We demonstrate that hypoxia-inducible factor-1α is a direct transcriptional suppressor of interferon regulatory factors, the transcriptional activators of type I IFN. These findings may aid in understanding and control of impaired IFN production by severe acute respiratory syndrome coronavirus 2 infection. Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
病毒逃避干扰素的十种策略。
影响因子：
30.3
作者：
García-Sastre A
通讯作者：
García-Sastre A
影响因子：
14.9
作者：
Chen KF;Lai YY;Sun HS;Tsai SJ
通讯作者：
Tsai SJ
影响因子：
44.1
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