Transient Infection Promotes Sustained Intervertebral Disc Degeneration Through the ATF-3/CHOP Pathway.

BACKGROUND

Infection with () is an important contributor to intervertebral disc degeneration (IDD). Endoplasmic reticulum stress (ERS) is a major pathway through which bacteria regulate cell fate. The aim of this study was to examine the role of ERS in -induced IDD.

METHODS

We assessed the -induced degeneration, apoptosis, and senescence of nucleus pulposus cells (NPCs) by Western blot, flow cytometry, and staining for β-galactosidase, and by magnetic resonance imaging/computed tomography (MRI/CT) imaging, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and histological staining. RNA sequencing was conducted to identify differentially expressed genes, while siRNA, lentiviral vectors, and (Atf3-KO) mice were utilized to confirm the role of ATF3 in persistent IDD following transient infection.

RESULTS

Following the eradication of , the expression of Aggrecan and collagen II in NPCs continued to decline, accompanied by an increase in the proportion of apoptotic and senescent cells. infection was shown to activate the Activating Transcription Factor 3 (ATF3)-CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) signaling pathway, leading to sustained swelling of the endoplasmic reticulum in NPCs. experiments further demonstrated that transient infection resulted in progressive IDD, activation of the ATF3-CHOP pathway, increased numbers of TUNEL-positive cells, and elevated P21 expression. Knockdown of ATF3 expression attenuated the -mediated increase in apoptotic and senescent cells, while -KO mice exhibited milder IDD compared to wild type (WT) mice, with fewer apoptotic cells and reduced P21 expression.

CONCLUSION

infection may lead to progressive IDD by triggering sustained ER stress and activating related signaling pathways. The ATF3-CHOP pathway may be an important target for alleviating the sustained disc degeneration caused by transient infection.