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PXN+ monocytes accelerate diabetic retinopathy progression and inflammaging via SELPLG-SELL axis-mediated immune chemotaxis and RAS modulation

Na Liang,Jing Li,Wenting Wang,Huifang Xu,Shaomin Peng

Published 2025 in Journal of the Renin-Angiotensin-Aldosterone System

ABSTRACT

Background Diabetic retinopathy (DR), a leading cause of vision loss, arises from chronic inflammation, vascular injury, and immune dysregulation. Aging-related mechanisms, including inflammaging, further exacerbate immune activation. The renin–angiotensin-aldosterone system (RAS) has been implicated in vascular dysfunction and chronic inflammation in DR. Paxillin (PXN), a cytoskeletal adaptor regulating immune cell migration, has not been fully explored in the context of DR and aging-related immune responses. Objective To determine how PXN+ monocytes contribute to DR progression, with a focus on SELPLG-SELL-mediated chemotaxis, PXN-RAS interactions, and age-related inflammatory remodeling. Methods Mendelian randomization (MR) and single-cell transcriptomics identified PXN as a putative driver of DR. Functional assays were performed in RAW264.7 macrophages with PXN overexpression or knockdown under high-glucose conditions, with or without Losartan treatment. qPCR, CCK-8, ELISA, flow cytometry, and immunoblotting were used to assess inflammatory and oxidative pathways. Results MR revealed a causal association between PXN and DR risk, highlighting the SELPLG-SELL axis as a major chemotaxis pathway. Single-cell RNA-seq showed PXN+ monocytes amplify T/NK cell crosstalk and immune infiltration. PXN overexpression promoted M1 polarization, upregulated SELL/SELPLG, increased IL-6, IL-17, and IL-23 secretion, and enhanced ACE-driven oxidative stress, attenuating Losartan's anti-inflammatory effects. These findings link PXN+ monocytes to inflammaging-like immune remodeling in DR. Conclusions PXN amplifies pro-inflammatory chemotaxis and immune aging in DR, undermining RAS inhibition. Targeting PXN may mitigate inflammaging-driven retinal inflammation and improve therapeutic responses in diabetic retinopathy. Graphical abstract This study identifies PXN+ monocytes as pivotal drivers of immune dysregulation and therapeutic resistance in diabetic retinopathy (DR), a microvascular complication closely linked to renin–angiotensin system (RAS) activity. PXN promotes Th1 polarization and recruits MKI67+ T/NK cells via the SELPLG–SELL axis, amplifying retinal inflammation through TNF-α, IFN-γ, and IL-2. It also induces M1 macrophage polarization, upregulates ACE, and increases oxidative stress. Notably, PXN overexpression abrogates the anti-inflammatory effects of the RAS inhibitor Losartan, revealing a novel mechanism of RAS blockade resistance. By integrating Mendelian randomization, single-cell RNA sequencing, and in vitro experiments, we establish PXN as a central immunomodulator, highlighting its therapeutic potential in DR and other RAS-driven inflammatory diseases.

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