The diagnostic value of the circadian rhythm gene KLF10 in anxiety-depressive disorders and its neuroimmune regulatory mechanisms

Abstract

Background

Anxiety-depressive disorder (ADD) is one of the important subtypes of depression, which has been shown to be closely related to neuroimmune abnormalities. Currently, specific biomarkers have not been identified as diagnostic, differential, and therapeutic targets. This study aimed to explore the molecular mechanisms and diagnostic biomarkers of ADD and elucidate its association with neuroinflammation.

Methods

Differentially expressed circadian rhythm-related genes were screened. Key genes were identified by machine learning. An ADD rat model was established using chronic restraint stress combined with corticosterone administration. Using AAV virus tools for KLF-10 overexpression and knockout (KLF10-OE and shKLF10), depression-like and anxiety-like behaviors were evaluated through behavioral experiments, pathological changes in the hippocampus and amygdala were observed by Nissl staining, cytokine levels were detected by ELISA, molecular co-localization was performed by RNAscope ISH and immunofluorescence, and molecular expression of NF-κB/NLRP3 pathway was detected by Western blot and qRT PCR.

Results

Nine circadian rhythm-related genes showed significant differential expression, with KLF10 identified as a diagnostic biomarker. KLF10 overexpression ameliorated depressive-like and anxiety-like behaviors, and reduced pro-inflammatory factors (IL-1β, TNF-α) and increased anti-inflammatory factors (IL-10, TGF-β) in both brain and serum, the treatment can be blocked by PMA. KLF10 suppressed IκB-α phosphorylation-mediated NF-κB nuclear translocation and inhibited downstream molecules.

Conclusion

KLF10 mitigates hippocampal-amygdala neuroinflammation by downregulating the NF-κB/NLRP3 pathway, thereby alleviating a ADD symptoms, and represents a potential diagnostic biomarker and therapeutic target.