SAMHD1 dysfunction induces IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells

Dysfunctional mutations in SAMHD1 cause Aicardi-Gouti & egrave;res Syndrome, an autoinflammatory encephalopathy with elevated interferon-alpha levels in the cerebrospinal fluid. Whether loss of function mutations in SAMHD1 trigger the expression of other cytokines apart from type I interferons in Aicardi-Gouti & egrave;res Syndrome is largely unclear. This study aimed to explore whether SAMHD1 dysfunction regulated the expression of IL-34, a key cytokine controlling the development and maintenance of microglia, in SH-SY5Y neural cells. We found that downregulation of SAMHD1 in SH-SY5Y cells resulted in the upregulation of IL-34 expression. The protein and mRNA levels of NF-kappa B p65, the transactivating subunit of a transcription factor NF-kappa B, were also upregulated in SAMHD1-knockdown SH-SY5Y cells. It was further found SAMHD1 knockdown in SH-SY5Y cells induced an upregulation of IL-34 expression through the canonical NF-kappa B-dependent pathway in which NF-kappa B p65, IKK alpha/beta and the NF-kappa B inhibitor I kappa B alpha were phosphorylated. Moreover, knockdown of SAMHD1 in SH-SY5Y cells led to the translocation of NF-kappa B p65 into the nucleus and promoted NF-kappa B transcriptional activity. In conclusion, we found SAMHD1 dysfunction induced IL-34 expression via NF-kappa B p65 in neuronal SH-SY5Y cells. This finding could lay the foundation for exploring the role of IL-34-targeting microglia in the pathogenesis of Aicardi-Gouti & egrave;res Syndrome.