---
title: "Oxidative stress–driven Treg dysregulation as a mechanistic link in SARD-associated interstitial l"
id: "frontiers-in-immunology-5-treg-dysregulation-in-the-oxidative-lung-milieu-an-emerging-mechanistic-link-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-5-treg-dysregulation-in-the-oxidative-lung-milieu-an-emerging-mechanistic-link-in"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1882853"
published_at: "2026-09-24T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Oxidative stress–driven Treg dysregulation as a mechanistic link in SARD-associated interstitial l
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1882853)
- **Published At:** 2026-09-24T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Systemic autoimmune rheumatic disease-associated interstitial lung disease (**SARD-ILD**) is a severe complication across multiple SARDs (RA, SSc, MPA, SjD, IIM, MCTD) and contributes substantially to morbidity and mortality. - Pulmonary fibrosis in SARD-ILD has been traditionally attributed to dysregulated fibroblast activation; current antifibrotic therapies mainly slow progression and often fail to reverse fibrosis. - Emerging evidence implicates immune microenvironment imbalance and **oxidative stress** as contributors to fibrotic remodeling in the lung. - Regulatory T cells (**Tregs**, CD4+ CD25+ Foxp3+) maintain immune tolerance; Treg dysfunction may involve numerical changes, altered phenotype/molecular programs, loss of lineage stability, or impaired suppressive capacity. - Oxidative stress may perturb Treg homeostasis through redox-sensitive regulation of **Foxp3** expression and stability, disruption of IL-2 signaling, mitochondrial dysfunction, and metabolic rewiring (OXPHOS/FAO dependence). - Experimental data (animal models and non-pulmonary autoimmune settings) indicate mechanisms by which oxidative stress and related pathways (e.g., ROS-driven SOCS3 upregulation, ACC1-regulated mitochondrial metabolism) destabilize Tregs; direct validation in human SARD-ILD is limited. - Loss of Treg lineage stability (e.g., Foxp3 instability mediated by BATF, CNS regulatory elements, IKZF1 dysfunction) can produce ex-Treg cells with effector-like features (e.g., Th17/Th1 skewing) and augment tissue inflammation in experimental settings. - Tregs have context-dependent roles in pulmonary fibrosis: they can limit inflammation, promote epithelial repair (via factors such as amphiregulin and KGF), and support macrophage maturation through IL-10, but may also foster fibroblast proliferation or pro-remodeling phenotypes under certain conditions. - Experimental models show that restoring Tregs (adoptive transfer or low-dose IL-2) can ameliorate pulmonary pathology, whereas Treg depletion impairs macrophage maturation and worsens fibrosis. - Human studies in IPF reveal impaired Treg suppressive function despite variable abundance; selected Treg phenotypes in progressive disease may exhibit reduced regulatory gene expression and pro-fibrotic activity. - The reviewed evidence is heterogeneous, largely derived from animal models, IPF, or other autoimmune conditions; direct mechanistic data from lung tissue or bronchoalveolar lavage fluid in patients with SARD-ILD are sparse. - The authors propose an oxidative stress–Treg dysregulation framework as a hypothesis-generating model to guide further mechanistic and translational studies; parts of the mechanistic sequence remain unproven in human SARD-ILD. - Details beyond the presented sections (including completed discussion of oxidative stress effects and subsequent sections) were not reported in the provided source excerpt.
## Clinical Analysis & Structured Key Points
Frontiers | Treg dysregulation in the oxidative lung milieu: an emerging mechanistic link in interstitial lung disease associated with systemic autoimmune rheumatic diseases REVIEW article Front. Immunol. , 24 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1882853 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Editor & Reviewers Edited by F D Fernanda Degobbi Tenorio Quirino dos Santos Lopes Reviewed by V M Vani Mishra X J Xiaokang Jia Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article REVIEW article Front. Immunol. , 24 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1882853 Treg dysregulation in the oxidative lung milieu: an emerging mechanistic link in interstitial lung disease associated with systemic autoimmune rheumatic diseases Y L Yanan Li † J W Jinghua Wang † H S Hongsheng Sun M F Min Fu * Department of Rheumatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, China Article metrics View details Abstract Systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD) is a fatal complication, in which the progression of pulmonary fibrosis has been closely linked to immune microenvironment imbalance and oxidative stress. Regulatory T cells (Tregs), as a central component of immune tolerance, play a crucial role in suppressing excessive inflammation. Current evidence suggests that oxidative stress may contribute to Treg dysregulation through several interrelated mechanisms, including redox-sensitive regulation of Foxp3 expression and stability, disruption of IL-2 signaling, and remodeling of the inflammatory microenvironment. However, the majority of the mechanistic evidence is derived from experimental models or related autoimmune and inflammatory conditions, with limited direct validation in patients with SARD-ILD. These proposed interactions may contribute to a self-reinforcing cycle of oxidative stress and Treg dysregulation, potentially promoting effector T-cell activation, fibroblast proliferation, and imbalanced inflammation and repair, thereby contributing to pulmonary fibrotic remodeling. This review integrates current evidence on the potential links among oxidative stress, Treg dysregulation, and pulmonary fibrosis in SARD-ILD, and proposes an emerging mechanistic framework to guide further investigation into their possible interactions and therapeutic implications. 1 Introduction Interstitial lung disease (ILD) comprises a heterogeneous group of inflammatory and fibrotic disorders that primarily affect the pulmonary mesenchyme and represents a major cause of morbidity and mortality in patients with systemic autoimmune rheumatic diseases (SARDs) ( 1 – 3 ). SARD-ILD may occur in rheumatoid arthritis (RA), systemic sclerosis (SSc), microscopic polyangiitis (MPA), Sjögren’s disease (SjD), idiopathic inflammatory myopathies (IIM)-including polymyositis, dermatomyositis, antisynthetase syndrome, and immune-mediated necrotizing myopathy-and mixed connective tissue disease (MCTD) ( 4 , 5 ). Notably, patients with SSc exhibit a high mortality rate, with a median survival of only 2–3 years in certain cases, thereby imposing a substantial burden on society and families ( 6 ). The conventional perspectives attribute pulmonary fibrosis primarily to dysregulated fibroblast activation ( 7 ). Accordingly, current clinical treatments primarily aim to inhibit fibroblast activation; however, this approach has shown limited efficacy, serving mainly to delay disease progression rather than reversing fibrosis, with some patients even developing resistance to treatment ( 8 ). Recent studies have implicated immune-microenvironment imbalance as a potential contributor to the development of SARD-ILD ( 9 – 11 ). Regulatory T (Treg) cells are essential for maintaining immune tolerance and homeostasis ( 12 ), and their functional impairment may be associated with the progression of pulmonary fibrosis. Furthermore, oxidative stress has been implicated in pulmonary fibrotic remodeling. Excessive ROS and RNS may damage cellular macromolecules and promote alveolar epithelial cell apoptosis, macrophage polarization, myofibroblast differentiation, and extracellular-matrix remodeling, thereby contributing to lung injury, inflammation, and fibrosis ( 13 , 14 ). However, much of this evidence derives from IPF and experimental pulmonary fibrosis models, and its direct relevance to human SARD-ILD remains to be established. Treg homeostasis is also sensitive to metabolic and redox perturbations: ACC1-regulated mitochondrial metabolism influences Treg suppressive function ( 15 ), whereas ROS-dependent SOCS3 upregulation can destabilize Tregs in experimental autoimmune settings ( 16 ). Taken together, oxidative stress may influence Treg stability through redox-sensitive regulation of Foxp3-associated pathways ( 16 , 17 ). In parallel, pro-inflammatory macrophage responses may remodel the immune microenvironment ( 18 ), whereas context-dependent metabolic cues may modulate Treg homeostasis and suppressive function ( 19 , 20 ). Collectively, these interacting processes may form a self-reinforcing pathological cycle ( 16 , 21 ) that disrupts immune homeostasis, promotes excessive effector T cells activation ( 22 , 23 ), abnormal proliferation of fibroblasts ( 24 ), and imbalanced macrophage-mediated inflammation and repair ( 25 ), thereby contributing to the progression of pulmonary fibrosis. Given this framework, an in-depth exploration of the molecular mechanisms by which oxidative stress disrupts local pulmonary immune tolerance, alongside a thorough elucidation of the Treg dysfunction in SARD-ILD, holds promise for identifying novel precision therapeutic targets. This narrative review summarizes and critically discusses relevant research advances, with particular attention to the strength, disease context, and translational relevance of the available evidence. Importantly, the collected evidence supporting the relationship among oxidative stress, Treg dysregulation, and pulmonary fibrosis is heterogeneous. Additionally, direct mechanistic evidence from patients with SARD-ILD, particularly from lung tissue or bronchoalveolar lavage fluid, remains limited. Since the majority of the mechanistic insights discussed in this review are derived from experimental pulmonary fibrosis models, other autoimmune diseases, or non-pulmonary inflammatory conditions, the findings of this review are considered supportive or hypothesis-generating evidence rather than direct proof of a causal pathway in human SARD-ILD. To maintain conceptual clarity and scientific rigor, we have distinguished direct SARD-ILD evidence from evidence extrapolated from related experimental and disease settings whenever possible. Accordingly, the proposed oxidative stress-Treg framework should be regarded as a potentially convergent but subtype-dependent hypothesis rather than as a unified mechanism established across RA-ILD, SSc-ILD, MPA-ILD, SjD-ILD, IIM-ILD, and MCTD-ILD. 2 Treg dysregulation in SARD-ILD Tregs are CD4 + CD25 + T cells that play an important role in maintaining immune tolerance and homeostasis, and are characterized by the expression of the transcription factor Foxp3. They regulate immune responses through multiple mechanisms, including interactions with other immune cells and the secretion of regulatory cytokines such as IL-10, IL-35, and TGF-β1 ( 11 , 26 ). In this review, Treg dysfunction is not inferred from changes in cell frequency alone. We distinguish four related but non-equivalent dimensions: numerical changes in Treg abundance; alterations in regulatory phenotype or molecular programs, including CD25/CTLA-4-associated regulation and IL-10/IL-35 production; loss of lineage stability, such as unstable Foxp3 expression or acquisition of effector-like features; and impaired suppressive capacity demonstrated by functional assays. The term “Treg dysfunction” is used most strictly for loss of lineage stability or suppressive capacity, whereas changes in Treg abundance, Foxp3 expression, or cytokine levels alone are treated as associated phenotypic observations unless supported by complementary functional evidence ( 12 , 26 ). Treg abnormalities have been increasingly investigated in SARD-ILD, yet the available evidence remains notably heterogeneous, including findings from patients with SARD-ILD, other ILD populations, related autoimmune diseases, and experimental models. For example, studies in patients with fibrotic ILD, including IPF and SARD-ILD, have shown that hilar lymphadenopathy is associated with poorer survival ( 27 ). Although these findings suggest that abnormal adaptive immune responses within lung-draining lymph nodes may be associated with disease progression, whether Treg dysregulation directly contributes to these changes remains unclear ( 27 ). Collectively, the current evidence supports a possible involvement of Treg dysregulation in SARD-ILD, yet the underlying mechanism remains to be fully established. 2.1 Treg phenotypic instability and altered Foxp3 expression One important aspect of Treg dysregulation is the alteration of Treg phenotype and lineage stability. Foxp3 is a key transcriptional regulator of Treg development, maintenance, and suppressive function ( 28 ). Reduced Foxp3 expression may be associated with impaired Treg stability and regulatory capacity, although changes in Foxp3 expression alone do not necessarily demonstrate loss of suppressive function. Recent studies have demonstrated that the transcription factor BATF is essential for maintaining Foxp3 stability. BATF has been identified as an important regulator of Foxp3 stability and Treg lineage maintenance, acting in part through its interaction with the CNS2 region of the Foxp3 locus ( 29 ). In mice with Treg-specific BATF deficiency, “ex-Treg” cells with Th17/effector T-cell-like characteristics have been observed, and the lungs are among the organs showing prominent immune-cell infiltration and tissue damage ( 30 ). These findings suggest that loss of Treg lineage stability may be accompanied by reduced regulatory characteristics and acquisition of effector-like features, with potential consequences for pulmonary immune homeostasis in experimental settings. However, they do not establish that the same BATF–Foxp3 mechanism operates in human SARD-ILD. Foxp3 expression and lineage stability are also coordinated by multiple regulatory elements within the Foxp3 locus, including CNS0, CNS2, and CNS3, which have distinct but complementary roles in Treg development and maintenance ( 31 ). Beyond their intrinsic regulation, Tregs also contribute to the control of excessive effector T-cell responses, including Th1-type inflammation ( 32 , 33 ). Impaired Treg regulation may therefore favor increased Th1 activity and IFN-γ production, potentially contributing to persistent inflammatory tissue injury. Various mechanisms under different pathological conditions further influence Treg stability. For example, studies in RA have suggested that IL-18 signaling may enhance Foxp3 ubiquitination and degradation, potentially contributing to altered Treg regulation ( 34 ). While this finding provides a possible mechanistic clue relevant to autoimmune inflammation, its direct relevance to pulmonary disease remains to be established. Similarly, experimental evidence suggests that loss of IKZF1 function can disrupt the stability of the Foxp3-associated regulatory complex, leading to Treg instability and increased IFN-γ production ( 35 ). These findings provide additional evidence that disruption of Treg stability may contribute to dysregulated inflammatory responses, but their specific relevance to SARD-ILD requires further investigation. Taken together, these findings suggest a possible relationship between impaired Treg lineage stability, altered inflammatory responses, and tissue remodeling. Nevertheless, the available evidence does not yet establish a definitive causal sequence from reduced Foxp3 expression to pulmonary fibrosis in human SARD-ILD. Accordingly, the pathway illustrated in Figure 1 should be interpreted as a proposed mechanistic framework that integrates evidence from diverse experimental and disease settings rather than as a confirmed causal cascade specific to SARD-ILD ( Figure 1 ). Figure 1 Proposed framework linking Foxp3 instability, Treg dysregulation, and pulmonary inflammatory and fibrotic remodeling. BATF supports Foxp3 transcription and Treg lineage stability through the CNS2 enhancer. Evidence from other autoimmune and inflammatory settings suggests that IL-18 signaling may promote Foxp3 ubiquitination and proteasomal degradation, whereas experimental IKZF1 deficiency disrupts the Foxp3-associated regulatory complex involving Eos and CtBP. These alterations may impair Foxp3 stability and contribute to the emergence of Foxp3-low/negative dysfunctional or ex-Treg-like cells. Stable Tregs normally restrain Th1 responses, whereas impaired Treg stability and regulatory capacity may favor enhanced Th1 activation and IFN-γ production, thereby sustaining inflammatory responses and tissue injury and potentially contributing to pulmonary inflammatory and fibrotic remodeling. Solid arrows indicate relationships supported by relatively direct evidence, whereas dashed arrows indicate proposed or indirect links. This framework integrates evidence from different experimental and disease settings; a direct causal sequence from Foxp3 instability to pulmonary fibrosis has not been established in human SARD-ILD. Created in BioRender. BATF, basic leucine zipper ATF-like transcription factor; CNS2, conserved non-coding sequence 2; CtBP, C-terminal-binding protein; Eos, Ikaros family zinc finger protein 4 (IKZF4); Foxp3, forkhead box P3; IFN-γ, interferon-γ; IKZF1, Ikaros family zinc finger protein 1; SARD-ILD, systemic autoimmune rheumatic disease-associated interstitial lung disease; Th1, T helper 1 cell; Treg, regulatory T cell. 2.2 Context-dependent roles of Tregs in pulmonary fibrosis Current evidence suggests that Treg dysregulation may be associated with pulmonary fibrotic remodeling, although the direction and magnitude of these effects vary across diseases and experimental settings. Experimental studies indicate that changes in Treg abundance can influence pulmonary inflammation and fibrotic remodeling. In the Fra-2 transgenic mouse model, impaired Treg homeostasis was associated with immune imbalance, pulmonary fibrosis, and vascular remodeling, while restoration of Treg populations through adoptive transfer or low-dose IL-2 significantly reduced these pulmonary abnormalities ( 36 ). These findings support a potential protective role of Tregs in this experimental setting. However, Treg effects may vary according to their functional state, the local tissue environment, and the stage of disease; Treg-mediated tissue repair may also carry profibrotic consequences under certain conditions. The balance between Treg and Th17/IL-17 responses represents one potentially relevant mechanism. In a bleomycin-induced murine model, inhibition of Th17 differentiation was associated with reduced fibrotic responses ( 37 ), while in a separate murine model of acute exacerbation of IPF (AE-IPF), IL-17 deficiency was accompanied by attenuated pulmonary inflammation and fibrosis together with enhanced Treg responses ( 38 ). These findings suggest a possible association between the Treg–Th17 balance and pulmonary fibrotic inflammation, although they do not establish that Tregs directly suppress fibrosis through inhibition of Th17/IL-17 responses. Tregs may also influence fibroblast activation and proliferation via tissue-repair and growth-related mediators; however, evidence for these effects is mainly derived from experimental models and other fibrotic diseases and should therefore be considered indirect in the context of SARD-ILD. Treg-derived amphiregulin (Areg) may have context-dependent effects on tissue remodeling. While experimental evidence has shown that Areg can promote fibroblast proliferation, Treg-specific Areg deficiency was associated with reduced allograft fibrosis and vasculopathy in chronic cardiac-allograft model ( 24 ). These findings suggest that Treg-mediated tissue repair and fibrotic remodeling may be closely interconnected, although the relevance of this mechanism in the context of SARD-ILD remains uncertain. Human studies in IPF further illustrate that Treg abundance and suppressive function are not equivalent. A study evaluating peripheral blood and bronchoalveolar lavage Tregs in patients with IPF reported globally impaired Treg suppressive function, which was associated with disease severity ( 39 ). In a separate study, Sema7A-expressing CD4 + CD25 + Foxp3 + Tregs were increased in patients with progressive IPF and exhibited reduced expression of regulatory genes, including IL-10. In the experimental component of the same study, adoptive transfer of Sema7A + Tregs promoted pulmonary fibrosis and remodeling in a TGF-β1-driven murine model ( 40 ). Although IPF is biologically distinct from SARD-ILD, these findings demonstrate that increased Treg abundance does not necessarily indicate preserved suppressive function and suggest that selected Treg phenotypes may acquire pro-remodeling properties in a fibrotic lung environment. Experimental studies further suggest that Treg depletion may affect pulmonary macrophage homeostasis. The heightened susceptibility of Treg-deficient mice to pulmonary fibrosis is closely linked to innate immune dysregulation. In transgenic mouse models, in vivo depletion of Tregs results in impaired maturation of monocyte-derived alveolar macrophages (Mo-AMs), characterized by decreased expression of the surface marker SiglecF. This maturation defect hinders the transition of macrophages from a pro-inflammatory to a reparative phenotype, thereby exacerbating disease severity and fibrosis. In these experimental models, Treg-derived IL-10 was identified as an important factor supporting macrophage maturation and limiting fibrotic progression ( 25 ). A study incorporating experimental lung injury models further showed that Tregs may promote alveolar epithelial repair through growth factors such as amphiregulin (Areg) and keratinocyte growth factor (KGF), while also limiting fibroproliferative remodeling by reducing the recruitment of bone marrow-derived collagen-producing cells through the CXCL12/CXCR4 axis ( 21 ). These findings suggest that Tregs may contribute to the tissue environment that favors repair over fibrosis in some settings, although the balance between their reparative and potentially pro-fibrotic effects may depend on the local microenvironment and disease stage ( 21 ). Overall, current evidence supports a potential but context-dependent role for Treg dysregulation in SARD-ILD and pulmonary fibrotic remodeling. Nevertheless, this evidence is derived from heterogeneous sources—including human SARD-ILD studies, other autoimmune or fibrotic diseases, and experimental models—which should not be considered equivalent. Changes in Treg abundance, phenotype, lineage stability, and suppressive function should therefore be interpreted separately. Direct mechanistic evidence from human SARD-ILD remains limited, and further disease- and tissue-specific studies are needed. 3 Oxidative stress and Treg dysregulation Treg metabolism is characterized by substantial reliance on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), which contribute to the maintenance of their metabolic fitness and suppressive programs ( 15 ). Mitochondrial integrity is likewise important for Treg suppressive capacity ( 15 , 41 ). Under oxidative stress, l
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