Cathepsin S from spinal cord microglia accelerates the degradation of perineuronal nets in neuropathic pain

Neuropathic pain (NP) caused by nerve damage or diseases affects the quality of life of patients. Analyzing differentially expressed genes (DEGs) can help researchers focus on the key molecular in the diseases. This study aims to explore the relationship between Cathepsin S (CTSS) and perineuronal nets (PNNs). Dataset GSE18803 was used for bioinformatics analysis firstly. Next, the changes in CTSS and PNNs in the spinal cord of spared nerve injury (SNI) rats were detected. Then, LPS was used to activate HAPI cells, and detected the CTSS level of the cellular supernatant. Furthermore, the vitro PNNs degradation experimental by active CTSS was executed. Finally, CTSS inhibitors were injected intrathecally into SNI rats and observed the changes of mechanical pain and PNNs. In dataset GSE18803, 15 hub genes related were identified of the NP. Meanwhile, the mRNA and protein levels of CTSS were significantly upregulated, and the PNNs degradation in the ipsilateral spinal cord lamina V of SNI rats. In vitro, CTSS levels were upregulated in the LPS-activated HAPI cellular supernatant. Moreover, CTSS promoted the degradation of PNNs by the vitro experimental. Furthermore, intrathecal injection of CTSS inhibitor significantly improved the mechanical threshold of SNI rats and inhibited PNN degradation in the spinal cord lamina V of SNI rats. Bioinformatics analysis indicates that the lysosomal pathway is crucial for NP progression. The lysosomal protein CTSS is upregulated in the spinal cord of SNI rats. Microglia in the lamina V aggravates NP development by releasing CTSS to degrade PNNs in SNI rats.