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Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

ABSTRACT: IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3's broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3 Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4-IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

SUBMITTER: Yanai H

PROVIDER: S-EPMC5960330 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

Yanai Hideyuki H Chiba Shiho S Hangai Sho S Kometani Kohei K Inoue Asuka A Kimura Yoshitaka Y Abe Takaya T Kiyonari Hiroshi H Nishio Junko J Taguchi-Atarashi Naoko N Mizushima Yu Y Negishi Hideo H Grosschedl Rudolf R Taniguchi Tadatsugu T

Proceedings of the National Academy of Sciences of the United States of America 20180430 20

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3's broad role in immunity and to more fully discern its role in various cellular subsets, we engineered <i>Irf3</i>-floxed mice to allow for the cell type-specific ablation of <i>Irf3</i> Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, imm ...[more]

PMID: 29712834

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Project description:Neutrophils are not only crucial immune cells for the neutralization of pathogens during infections, but they are also key players in tissue repair and cancer. Several methods are available to investigate the in vivo role of neutrophils in these conditions, including the depletion of neutrophils with neutralizing antibodies against Ly6G, or the blockade of neutrophil recruitment with CXCR2 inhibitors. A limited number of transgenic mouse models were generated that rely on the disruption of genes important for neutrophil development or on the injection of diphtheria toxin to induce neutrophil ablation. However, these methods have various limitations, including a lack of neutrophil specificity, a lack of long-term efficacy, or a lack of the ability to conditionally deplete neutrophils. Therefore, we generated a transgenic mouse model for the inducible and reversible ablation of neutrophils using the ATTAC (Apoptosis Through Targeted Activation of Caspase 8) approach. With the ATTAC strategy, which relies on the expression of the caspase 8-FKBP fusion protein, apoptosis is induced upon administration of a chemical dimerizer (FK506 analogue) that facilitates the dimerization and activation of caspase 8. In order to achieve specific neutrophil depletion, we cloned the ATTAC construct under the human migration inhibitory factor-related protein 8 (hMRP8) promotor. The newly generated hMRP8-ATTAC mice expressed high levels of the transgene in neutrophils, and, as a consequence, dimerizer injection induced an efficient reduction of neutrophil levels in all the organs analyzed under homeostatic conditions. In situations with extensive pressure on the bone marrow to mobilize neutrophils, for instance in the context of cancer, effective neutrophil depletion in this model requires further optimization. In conclusion, we here describe the generation and characterization of a new transgenic model for conditional neutrophil ablation and highlight the need to improve the ATTAC strategy for the depletion of large numbers of rapidly generated short-lived cells, such as neutrophils.

Dataset Information

Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

Publications

Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

Similar Datasets

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