[KLF10 overexpression alleviates neuroinflammation and anxiety-depressive disorder in rats by downregulating the...

To elucidate the neuroimmune regulatory mechanism of the circadian rhythm gene KLF10 as a biomarker for anxiety depressive disorder (ADD).

The differentially expressed circadian rhythm genes were screened using human peripheral blood gene chip data from the GEO database (including 64 healthy individuals, 62 patients with major depressive disorder [MDD], and 59 with ADD) in conjunction with the MSigDB database. Weighted gene co-expression network analysis and machine learning models were employed to identify the core genes, followed by KEGG pathway enrichment analysis and evaluation of their diagnostic efficacy using ROC curves. In a male SD rat model of ADD induced by chronic restraint and corticosterone stress, the changes in depressive-like behaviors, hippocampal and amygdala pathologies, levels of inflammatory and pro-inflammatory cytokines, co-localization of KLF10 and p-p65 expression, and expression levels of NF‑κB/NLRP3 pathway molecules were examined following stereotactic AAV virus injection into the lateral ventricle for KLF10 overexpression.

Compared with healthy individuals, the depressive patients showed differential expressions of 9 circadian rhythm genes. Compared with the MDD patients, the patients with ADD had significantly higher immune infiltration scores with upregulated NOD-like receptor and NF‑κB signaling pathways. The specific biomarker KLF10 demonstrated a diagnostic efficacy of 0.885. In the rat models of AOD, KLF10 overexpression significantly ameliorated depression- and anxiety-like behaviors, restored the balance between the pro- and anti-inflammatory cytokines, and improved hippocampal and amygdala pathologies. KLF10 overexpression also markedly upregulated NFKBIA mRNA, downregulated NLRP3 and RELA mRNAs, and reduced protein expressions of p-IκB‑α, p-p65, and NLRP3 in the brain tissues of the rats.

KLF10 overexpression ameliorates ADD behaviors in rats by inhibiting hippocampal-amygdala inflammation via downregulating the NF‑κB/NLRP3 pathway, suggesting the potential of KLF10 as a diagnostic biomarker and therapeutic target for AOD.