Arid5a exacerbates IFN-γ–mediated septic shock by stabilizing T-bet mRNA

Abstract

Adenine-thymine (AT)-rich interactive domain containing protein 5a (Arid5a) is an RNA-binding protein that has been shown to play an important immune regulatory function via the stabilization of IL-6 and STAT3 mRNA. However, the role of Arid5a in the overwhelming and uncontrolled immune response that leads to septic shock is unknown. Here, we report that Arid5a-deficient mice are highly resistant to lipopolysaccharide (LPS)-induced endotoxic shock and secrete lower levels of major proinflammatory cytokines, including IFN-γ, IL-6, and TNF-α, than WT mice in response to LPS. Arid5a deficiency resulted in decreased levels of IFN-γ under Th1 cell conditions, in which T-box expressed in T cells (T-bet) mRNA expression was inhibited. Arid5a bound to the conserved stem loop structure of the 3′UTR of T-bet and stabilized its mRNA. Arid5a-deficient mice were also resistant to Propionibacterium acnes-primed LPS injection, which is considered to be a T-cell-mediated IFN-γ dependent endotoxic shock mouse model. Thus, regulation of IFN-γ by Arid5a via the stabilization of T-bet mRNA in Th1 cells contributes to the development of septic shock in mice. In addition, our previous study suggests that Arid5a control the IL-6 level in vivo in response to LPS by stabilization of IL-6 mRNA. We also observed that neutralization of IFN-γ and IL-6 significantly recovered the mice from endotoxic shock. Taken together, we conclude that Arid5a regulates the augmentation of IL-6 and IFN-γ in response to LPS, which possibly works synergistically for amplification of various other cytokines that ultimately cause the development of septic shock in mice.septic shock | Arid5a | IFN-γ | T-bet | IL-6

Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker

“…Information on functioning of ARID5A is limited. ARID5A is reported to be a RNA binding protein, which helps in stability of IL‐6 mRNA and T‐bet, thereby controlling the inflammatory response (Masuda et al, ; Zaman et al, ). It has been also recently reported that ARID5A decides cell fate of naive CD4(+)T cells and its deficiency causes T cell activation (Sprent & Surh, ).…”

Implications of IL-6 Targeting Therapy for Sepsis

“…More recently, we also observed not only therapeutic effects of blockade of two different cytokines, IL-6 and IFNγ, against sepsis development, but also the novel function of Arid5a in the development of naïve T cells into Th1 cells by stabilizing T-bet mRNA [14]. Arid5a-deficient mice in Propionibacterium acnes-primed endotoxin shock model, which elicit Th1 responses, showed lower levels of IFNγ, IL-6 and TNFα, with higher survival rate.…”

Post‐transcriptional control of immune responses and its potential application

“…Arid5a expression is induced upon the stimulation of macrophages by LPS, IL‐6 and IL‐1β and stabilises Il6 mRNA by counteracting Regnase‐1‐mediated mRNA decay . It is also reported that Arid5a binds to T‐box‐containing protein expressed in T cells (T‐bet) and signal transducer and activator of transcription 3 (Stat3) mRNA to enhance the inflammation . Moreover, Arid5a is reported to promote translation of Nfkbiz and Cebpb mRNA .…”

“…42 It is also reported that Arid5a binds to T-box-containing protein expressed in T cells (T-bet) and signal transducer and activator of transcription 3 (Stat3) mRNA to enhance the inflammation. 43,44 Moreover, Arid5a is reported to promote translation of Nfkbiz and Cebpb mRNA. 45 Thus, these studies demonstrate that Arid5a is a positive regulator of immune responses which antagonises Regnase-1 function.…”

“…While its mechanism of action is independent of a-KG and iron, it has also been shown to selectively inhibit FTO rather than ALKBH5. 44 These and future studies will provide valuable compounds that specifically target individual demethylases, all of which should be tested in animal models in the future.…”