PP2A dysfunction mediated by PPP2R1A deficiency drives cGAS-STING-dependent hyperinflammation in SLE CD14⁺ monocytes

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Systemic lupus erythematosus (SLE) is characterized by a hyperinflammatory response in monocytes.
• The precise mechanisms underlying this aberrant innate immune activation remain incompletely understood.
• Protein phosphatase 2A (PP2A) is a key regulator of cellular processes, but its role in SLE pathogenesis is unclear.

Purpose of the Study:

• To investigate the role of Protein Phosphatase 2A (PP2A) dysfunction in the hyperinflammatory response of systemic lupus erythematosus (SLE) monocytes.
• To elucidate the functional link between PP2A subunit dysregulation, reduced enzymatic activity, and aberrant innate immune activation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor 1 (STING) pathway.
• To evaluate the therapeutic potential of modulating PP2A activity in SLE monocytes.

Main Methods:

• Isolated CD14+ monocytes from 88 SLE patients and 40 healthy controls (HCs).
• Analyzed PP2A subunit mRNA expression, PP2A phosphatase activity, and inhibitory phosphorylation (PP2Ac-Y307).
• Modulated PP2A activity pharmacologically (LB-100 inhibition in HCs, FTY720 activation in SLE) and assessed cGAS-STING pathway activation, interferon-stimulated gene (ISG) expression, and cytokine secretion.

Main Results:

• SLE monocytes showed decreased PPP2R1A expression, reduced PP2A activity, and increased PP2Ac-Y307 phosphorylation.
• PP2A inhibition in HCs monocytes amplified cGAS-STING-dependent ISG expression and cytokine release, mimicking SLE phenotype.
• FTY720-mediated PP2A activation in SLE monocytes significantly reduced the exaggerated immune response.

Conclusions:

• PP2A hypofunction is a critical pathogenic driver in SLE monocytes, contributing to hyperinflammation.
• The downregulation of PPP2R1A and subsequent reduction in PP2A activity are key pathological mechanisms.
• Restoring PP2A activity, for example, with the agonist FTY720, effectively mitigates dysregulated innate immune responses, presenting a promising therapeutic strategy for SLE.