Dusp8, also known as HVH-5, is a dual-specificity phosphatase and a member of the DUSPs family. It dephosphorylates and inactivates kinases like JNK, p38 MAPK, and ERKs in the mitogen-activated protein kinase (MAPK) signaling pathway, playing a crucial role in phosphorylation-mediated signal transduction involved in cell oxidative stress response, apoptosis, and various diseases [2]. Genetic models such as knockout (KO) and conditional knockout (CKO) mice are valuable for studying its functions in vivo.

In T-cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, DUSP8 was found to interact with Pur-α, stimulate IL-9 gene expression, and promote Th9 differentiation. Mechanistically, it dephosphorylated Pur-α, leading to its nuclear export and IL-9 transcriptional activation. T-Dusp8-cKO mice showed reduced IL-9 and Th9-mediated immune responses in the allergic asthma model, and these reductions were reversed by Pur-α knockout [1]. Dusp8 KO mice also suffered from mildly impaired spatial learning, increased locomotor activity, and elevated anxiety. Phospho-Erk levels were higher in their hippocampi, and human carriers of the DUSP8 allelic variant SNP rs2334499:C > T had reduced volumes of hippocampal subregions [3]. In a spinal nerve ligation (SNL) rat model, AAV-mediated DUSP8 over-expression ameliorated SNL-induced neuropathic pain, attenuated neuronal death, and mitigated neuroinflammation and microglial activation by suppressing NF-κB signaling [4].

In conclusion, Dusp8 is an important regulator in the MAPK signaling pathway. Studies using KO and CKO mouse models have revealed its roles in allergic inflammation, hippocampal function, and neuropathic pain. These findings contribute to our understanding of the underlying mechanisms of related diseases and may provide potential therapeutic targets for asthma, atopic dermatitis, and neuropathic pain.