The Unfolded Protein Response Sensor IRE1 Regulates Activation of In Vitro Differentiated Type 1 Conventional DCs with Viral Stimuli

被引:1
作者
Medel, Bernardita [1 ]
Ignacio Bernales, Jose [1 ]
Lira, Alonso [1 ]
Fernandez, Dominique [1 ]
Iwawaki, Takao [2 ]
Vargas, Pablo [3 ]
Osorio, Fabiola [1 ]
机构
[1] Univ Chile, Immunol Program, Lab Immunol & Cellular Stress, Inst Biomed Sci,Fac Med, Santiago 8380453, Chile
[2] Kanazawa Med Univ, Med Res Inst, Dept Life Sci, Div Cell Med, 1-1 Daigaku, Kahoku, Ishikawa 9200293, Japan
[3] Univ Paris Cite, INSERM UMR S1151, CNRS UMR S8253, Leukomot Lab,Inst Necker Enfants Malad, F-75015 Paris, France
关键词
dendritic cells; cDC1s; unfolded protein response; IRE1; proinflammatory cytokines; ENDOPLASMIC-RETICULUM STRESS; DENDRITIC CELLS; THERAPEUTIC TARGET; GENERATION; INDUCTION; DECAY; XBP-1;
D O I
10.3390/ijms241210205
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Type 1 conventional dendritic cells (cDC1s) are leukocytes competent to coordinate antiviral immunity, and thus, the intracellular mechanisms controlling cDC1 function are a matter of intense research. The unfolded protein response (UPR) sensor IRE1 and its associated transcription factor XBP1s control relevant functional aspects in cDC1s including antigen cross-presentation and survival. However, most studies connecting IRE1 and cDC1 function are undertaken in vivo. Thus, the aim of this work is to elucidate whether IRE1 RNase activity can also be modeled in cDC1s differentiated in vitro and reveal the functional consequences of such activation in cells stimulated with viral components. Our data show that cultures of optimally differentiated cDC1s recapitulate several features of IRE1 activation noticed in in vivo counterparts and identify the viral analog Poly(I:C) as a potent UPR inducer in the lineage. In vitro differentiated cDC1s display constitutive IRE1 RNase activity and hyperactivate IRE1 RNase upon genetic deletion of XBP1s, which regulates production of the proinflammatory cytokines IL-12p40, TNF-& alpha; and IL-6, Ifna and Ifnb upon Poly(I:C) stimulation. Our results show that a strict regulation of the IRE1/XBP1s axis regulates cDC1 activation to viral agonists, expanding the scope of this UPR branch in potential DC-based therapies.
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页数:16
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