Background: Ankylosing spondylitis (AS) is an autoinflammatory disease characterized by elevated levels of inflammatory cytokines, such as interleukin 1β (IL-1 β, tumor necrosis factor-α (TNF-α), and IL-6, which are secreted predominantly by innate immune cells. Currently, the regulatory mechanisms underlying cytokine production and chronic inflammation in AS are not well understood. Protein phosphatase magnesium-dependent 1A (PPM1A) is a serine/threonine phosphatase involved in the regulation of transforming growth factor β (TGF-β), nuclear factor κB (NF-κB), and Wnt signaling. Previous studies have identified a negative correlation between PPM1A levels in the peripheral blood mononuclear cells (PBMCs) of patients with AS and Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) [1]. Furthermore, in vivo experiments have demonstrated that PPM1A expression in macrophages decreases in response to the induction of inflammation [1].

Objectives: To investigate the role of PPM1A in macrophage-mediated cytokine secretion, as well as its contribution to chronic inflammation in AS.

Methods: Two AS-related gene expression profiles were analyzed using datasets from the Gene Expression Omnibus (GEO). For the in vivo experiments, SKG mice injected with curdlan were utilized as a model of AS. The expression levels of PPM1A in macrophages were measured using flow cytometry. To investigate the role of PPM1A in macrophages, PPM1A ^fl/fl ;LysM-Cre mice were utilized. To induce inflammasome activation, PPM1A ^fl/fl ;LysM-Cre mice were intraperitoneally injected with LPS, and the levels of IL-1β and TNF-α were measured using ELISA.

Results: The analysis of GEO datasets from patients with AS showed a negative correlation between PPM1A expression and IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and IL-23A expression in the differentiated macrophages; however, there was no significant correlation between PPM1A levels and TNFα and IL-6 levels. Using flow cytometry, we observed that PPM1A expression in macrophages isolated from SKG mice, a well-established model of AS, was reduced. To decipher the role of PPM1A in macrophages, PPM1A ^fl/fl ;LysM-Cre mice were injected with LPS. We observed that PPM1A ^fl/fl ;LysM-Cre mice had a lower survival rate than that of control mice. Furthermore, IL-1b expression levels, but not TNFα levels, in serum and peritoneal lavage fluid were significantly increased compared to those in control LysM-Cre mice.

Conclusion: These findings suggest that the loss of PPM1A in macrophages increases IL-1β secretion, contributing to inflammation in AS.

REFERENCES: [1] Kwon OC, Choi B, Lee EJ, et al. Negative Regulation of Osteoclast Commitment by Intracellular Protein Phosphatase Magnesium-Dependent 1A. Arthritis Rheumatol. May 2020;72(5):750-760. doi:10.1002/art.41180.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.