Role of PPARγ, IL-1β Blockers, and TGF-β1 in Diabetic Wound Healing: Mechanisms and Therapeutic Potential

Riani Erna; Arief S. Kartasasmita; Shanti F. Boesoirie; Wijana Hasansulama; Ramzi Amin

doi:10.22467/jwmr.2025.03272

Journal of Wound Management and Research > Volume 21(2); 2025 > Article

Erna, Kartasasmita, Boesoirie, Hasansulama, and Amin: Role of PPARγ, IL-1β Blockers, and TGF-β1 in Diabetic Wound Healing: Mechanisms and Therapeutic Potential

Review Article

Journal of Wound Management and Research 2025; 21(2): 58-66.

Published online: June 30, 2025

DOI: https://doi.org/10.22467/jwmr.2025.03272

Role of PPARγ, IL-1β Blockers, and TGF-β1 in Diabetic Wound Healing: Mechanisms and Therapeutic Potential

Riani Erna^1,²

, Arief S. Kartasasmita³

, Shanti F. Boesoirie³

, Wijana Hasansulama⁴

, Ramzi Amin²

¹Doctoral Program, University of Padjadjaran, Bandung, Indonesia

²Ophthalmology Department, University of Sriwijaya, Palembang, Indonesia

³Ophthalmology Department, University of Padjadjaran, Bandung, Indonesia

⁴Otorhinolaryngology, Head and Neck Surgery Department, University of Padjadjaran, Bandung, Indonesia

Corresponding author: Riani Erna, MD Doctoral Program, University of Padjajaran, Bandung 45363, Indonesia E-mail: rianierna.opt@gmail.com

Received March 20, 2025 Revised April 25, 2025 Accepted April 28, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Diabetic foot ulcers are a major diabetes complication, particularly in regions with high prevalence and limited access to advanced care. Impaired healing in diabetic foot ulcers results from chronic inflammation, poor angiogenesis, extracellular matrix dysfunction, and metabolic imbalances. This review examines the roles of peroxisome proliferator-activated receptor gamma (PPARγ), interleukin-1 beta (IL-1β) blockers, and transforming growth factor beta 1 (TGF-β1) in diabetic wound healing. PPARγ suppresses inflammation and promotes tissue repair, but its function is often impaired in diabetes. IL-1β sustains inflammation and delays macrophage transition from M1 to M2, while TGF-β1 dysregulation disrupts collagen synthesis and extracellular matrix remodeling, contributing to fibrosis or delayed healing. These pathways are also implicated in diabetic retinopathy, where chronic inflammation and impaired angiogenesis worsen tissue damage. PPARγ agonists (e.g., rosiglitazone), IL-1β blockers (e.g., anakinra, canakinumab), and TGF-β1 modulators offer promising therapeutic strategies. While preclinical studies show potential, further clinical research is needed to refine treatment approaches and improve patient outcomes.

Key Words: Diabetic foot; Wound healing; Peroxisome proliferator-activated receptors; Transforming growth factor beta; Interleukin-1

Introduction

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia due to defects in insulin secretion, action, or both [1]. It includes several subtypes, with type 1 (T1DM) and type 2 diabetes (T2DM) being the most prevalent [1,2]. In addition to poor glucose control, DM leads to widespread vascular complications—such as retinopathy, nephropathy, and peripheral neuropathy—that hinder wound healing and elevate the risk of developing diabetic foot ulcers (DFUs) [2,3].

DFUs are full-thickness skin lesions that arise due to neuropathy and vascular complications, often leading to infection, gangrene, and amputation [4]. Globally, DFUs affect 6.3% of diabetics [5,6], with higher prevalence in Indonesia due to underdiagnosis and poor glycemic control [7-9]. DFUs are prone to recur, with approximately 65% of cases reappearing within 3 to 5 years, and are linked to considerable illness and death [10].

The wound healing process in DFUs is impaired due to chronic inflammation, reduced angiogenesis, delayed tissue remodeling, infection, and antibiotic resistance [11-13]. Peripheral arterial disease and neuropathy further limit blood flow, leading to ischemia and necrosis [14]. Poor glycemic control, nutritional deficiencies, and comorbidities such as kidney disease and obesity exacerbate healing delays [11,14]. Treatment challenges include limited access to advanced therapies, inconsistent use of dressings, and high amputation rates despite surgical advancements [13,15].

At the molecular level, peroxisome proliferator-activated receptor gamma (PPARγ), interleukin-1 beta (IL-1β), and transforming growth factor beta 1 (TGF-β1) play crucial roles in diabetic wound healing [16-18]. PPARγ is an anti-inflammatory nuclear receptor that is suppressed in DFUs due to persistent IL-1β activity, which promotes a pro-inflammatory macrophage phenotype and delays healing [16]. Meanwhile, TGF-β1 regulates fibroblast activation and extracellular matrix (ECM) remodeling [17,19], but its dysregulation in diabetes disrupts tissue repair [17,20]. Therapeutic approaches targeting these pathways, including IL-1β blockers (e.g., anakinra), PPARγ agonists (e.g., rosiglitazone), and TGF-β1 modulators, offer promising strategies to restore wound healing and reduce DFU-related complications.

This review aims to explore the molecular interplay between PPARγ, IL-1β, and TGF-β1 in diabetic wound healing, highlighting their roles in inflammation, ECM remodeling, and angiogenesis. Furthermore, we discuss the therapeutic potential of targeting these pathways through IL-1β blockers (e.g., anakinra), PPARγ agonists (e.g., rosiglitazone), and TGF-β1 modulators as novel strategies to enhance diabetic wound healing and reduce DFU-related complications.

Pathophysiology of diabetic wounds

DFUs result from a complex interplay of systemic and local factors [21,22]. On a macroscopic level, chronic hyperglycemia induces peripheral neuropathy, vasculopathy, and immune dysfunction, all of which contribute to wound chronicity [22]. Neuropathy leads to loss of protective sensation, repetitive trauma, and unnoticed injuries [21]. Microvascular and macrovascular complications impair blood flow, limiting oxygen and nutrient delivery to tissues [23]. Additionally, impaired leukocyte chemotaxis and function reduce the ability to fight infection, making wounds more susceptible to colonization and biofilm formation [16,24]. These systemic dysfunctions establish a hostile microenvironment for healing, which is further exacerbated by cellular and molecular impairments (Fig. 1) [17,25].

Hyperglycemia impairs diabetic wound healing through metabolic, vascular, and immune dysregulation, leading to delayed recovery and increased complications [26]. In DM, hyperglycemia leads to osmotic diuresis and significant fluid loss, contributing to intravascular volume depletion and impaired perfusion. These hemodynamic changes, along with endothelial dysfunction, reduce oxygen delivery to tissues, thereby exacerbating vascular complications and delaying wound healing [23,26].

Immune dysfunction in diabetes suppresses neutrophil function, reducing bacterial clearance and increasing infection risk [24]. Persistent hyperglycemia triggers chronic inflammation, with elevated IL-1β and tumor necrosis factor alpha (TNF-α) delaying the transition to the proliferative phase [27]. IL-1β overexpression promotes M1 macrophage polarization, inhibits fibroblast migration, and upregulates matrix metalloproteinases (MMPs), leading to ECM degradation. Additionally, IL-1β activates p38 mitogen-activated protein kinase (MAPK), amplifying inflammatory cascades and further delaying granulation tissue formation [27,28].

Hyperglycemia also disrupts collagen synthesis and ECM remodeling, accelerating advanced glycation end-product formation, which induces collagen cross-linking and fibroblast apoptosis, reducing skin elasticity and impairing closure [26,29]. TGF-β1 deficiency in diabetes further delays re-epithelialization, collagen organization, and granulation tissue formation, while excessive TGF-β1 may exacerbate fibrosis and scarring [30,31]. Neuropathy impairs pain perception, delaying wound detection and increasing the risk of infection and gangrene [32].

PPARγ plays a critical anti-inflammatory role by suppressing IL-1β-driven inflammation and promoting angiogenesis and ECM repair [33]. However, chronic IL-1β activity inhibits PPARγ, prolonging inflammation and impairing tissue regeneration [27]. IL-1β blockade restores PPARγ activity, allowing macrophage transition to the M2 phenotype, while TGF-β1 supplementation counteracts IL-1β-induced MMP overexpression, balancing ECM remodeling and angiogenesis [27,30,31].

Chronic inflammation in diabetic wounds also activates damage-associated molecular patterns and pattern recognition receptors, perpetuating immune dysregulation even after pathogen clearance [25,34]. IL-1β dominance, alongside TGF-β suppression and IL-6 activation, further drives macrophage polarization toward a pro-inflammatory state. Meanwhile, immune suppression via anti-inflammatory cytokines and regulatory T cells (Tregs), including indoleamine 2,3-dioxygenase, arginase, and inducible nitric oxide synthase, disrupts immune balance, impairing wound healing [25,34-36].

Role of PPARγ in diabetic wound healing

PPARγ is a nuclear receptor that regulates lipid metabolism, glucose homeostasis, and inflammation [37,38]. It belongs to the PPAR family (PPARα, PPARβ/δ, and PPARγ) and is activated by fatty acids, prostaglandins (e.g., PGJ₂), and arachidonic acid metabolites. PPARγ exerts its effects through transcriptional regulation, influencing inflammation, ECM remodeling, and tissue repair [39].

PPARγ modulates gene expression through ligand-dependent transcriptional control, involving transactivation and transrepression mechanisms:

· Transactivation: PPARγ forms a heterodimer with the retinoid X receptor, binding to peroxisome proliferator response elements in DNA to regulate target genes [40,41]. Ligand binding induces conformational shifts, recruiting coactivators (e.g., SRC1, CBP) and initiating chromatin remodeling, enhancing transcription [40-42].

· Transrepression: PPARγ suppresses inflammation by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 signaling, stabilizing corepressor complexes at inflammatory gene promoters [40,41].

· Ligand dynamics: synthetic ligands (e.g., rosiglitazone) bind to the ligand-binding domain, inducing unique conformational changes that enhance coactivator recruitment and anti-inflammatory effects [42,43].

PPARγ exists in two isoforms: PPARγ1 (ubiquitously expressed, involved in metabolic regulation) and PPARγ2 (predominantly in adipose tissue, enhancing transcriptional activation at low ligand concentrations) [41]. PPARγ exerts anti-inflammatory effects by suppressing TNF-α, IL-1β, IL-6, IL-8, and monocyte chemoattractant protein-1 in macrophages, downregulating NF-κB, and promoting apoptotic cell clearance via CD36 and MerTK upregulation [44-46]. PPARγ activation also shifts macrophages from M1 (pro-inflammatory) to M2 (pro-healing) phenotypes, facilitating angiogenesis, collagen deposition, and granulation tissue formation [44,46]. Its role extends to reducing oxidative stress (via the Nrf2/ARE pathway) and mitigating fibrosis by suppressing TGF-β1 and MMP expression [46].

PPARγ agonists such as rosiglitazone and pioglitazone have been shown to enhance granulation tissue formation, angiogenesis, and ECM remodeling in diabetic wounds [47]. Studies indicate that pioglitazone reduces MMP-9 levels, suppressing collagen degradation and improving wound closure [18]. Mirza et al. [16] found that IL-1β suppresses PPARγ in diabetic wounds, delaying healing, while IL-1β inhibition restores PPARγ function, promoting macrophage transition to an M2 phenotype and improving epithelialization.

Additionally, Chen et al. [44] reported that PPARγ-deficient mice exhibited impaired collagen deposition, angiogenesis, and apoptotic cell clearance, further emphasizing PPARγ’s role in tissue regeneration. While PPARγ activation enhances wound healing in macrophages, some studies suggest it may inhibit fibroblast differentiation into myofibroblasts, potentially delaying repair [44].

Role of IL-1β blockers in diabetic wound healing

IL-1β is a pro-inflammatory cytokine that plays a central role in inflammation [48,49]. It is initially produced as an inactive 31 kDa pro-form (pro-IL-1β), which becomes biologically active (17 kDa) following cleavage by caspase-1 through the action of inflammasomes [48,50]. Monocytes, macrophages, and dendritic cells are the main sources of IL-1β, releasing it in response to tissue damage and pathogen-associated molecular patterns, thereby promoting inflammatory and immune processes. Its biological function includes stimulating lymphocyte proliferation, neutrophilia, and acute-phase protein production, but it also promotes tissue damage by upregulating chemokines, inflammatory cytokines, and MMPs [50,51]. While IL-1β is critical for host defense, its persistent activation contributes to chronic inflammation, autoimmune diseases, and cancer progression [48,50].

IL-1β exerts its effects through receptor-mediated signaling, binding to IL-1 receptor type I (IL-1R1) to activate downstream pathways. The NF-κB pathway induces pro-inflammatory cytokines such as TNF-α and IL-6, while the p38 MAPK pathway modulates apoptosis and synaptic plasticity in neurons [52,53]. Additionally, IL-1β activates the MEK/ERK pathway, which upregulates Bax expression, promoting apoptosis. These signaling cascades amplify inflammatory responses, increasing tissue degradation and impairing healing [54,55]. Elevated IL-1β levels are associated with inflammatory diseases, tissue fibrosis, and pain sensitization, where its role in glial-neuronal interactions contributes to chronic pain and hyperalgesia [53,56,57].

In diabetic wounds, IL-1β is a key driver of chronic inflammation and impaired healing. It promotes M1 macrophage polarization by activating NF-κB and NOD-like receptor family pyrin domain containing 3 inflammasomes, leading to sustained secretion of pro-inflammatory cytokines (TNF-α, IL-17) [58,59]. This creates a self-reinforcing inflammatory cycle that delays wound resolution [56,60]. Additionally, IL-1β inhibits M2 macrophage polarization by downregulating TGF-β and IL-10, which are crucial for tissue repair [59,61]. By upregulating MMP-9 via the p38 MAPK pathway, IL-1β further disrupts fibroblast migration and ECM remodeling, contributing to prolonged inflammation and delayed wound closure [59].

Given its significant role in chronic inflammation, targeting IL-1β has emerged as a promising therapeutic strategy for diabetic wound healing [56,59]. IL-1β blockade promotes macrophage reprogramming, shifting the immune balance from an M1-dominated inflammatory state to an M2 pro-healing phenotype [61,62]. This process enhances angiogenesis, ECM remodeling, and granulation tissue formation by restoring levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), and insulin-like growth factor 1 (IGF-1) while downregulating MMP-9 to improve fibroblast function [27,33,63]. Several IL-1β inhibitors have been developed, including anakinra, canakinumab, and rilonacept [50,64]. Anakinra is a recombinant IL-1R antagonist (IL-1Ra) that blocks IL-1α/β binding to IL-1R1 [64,65], while canakinumab is a monoclonal antibody that selectively neutralizes IL-1β [65,66]. Rilonacept functions as a soluble decoy receptor, preventing IL-1β from triggering inflammatory signaling [64,66]. Newer agents, such as lutikizumab and gevokizumab, are being investigated for their ability to modulate chronic inflammatory diseases and metabolic disorders [57,67].

The therapeutic potential of IL-1β inhibition has been demonstrated in both preclinical and clinical studies. Mirza et al. [63] reported that IL-1β blockade in human diabetic subjects and experimental animal models led to enhanced wound closure, re-epithelialization, angiogenesis, and collagen deposition. This was attributed to a shift from a pro-inflammatory macrophage phenotype (M1) to a healing-associated phenotype (M2), supported by reduced expression of IL-1β, MMP-9, and TNF-α, alongside increased levels of CD206, IGF-1, and TGF-β [63]. In another study, Tan et al. [33] demonstrated that topical delivery of IL-1Ra fused with placental growth factor improved diabetic wound healing by enhancing ECM stabilization and promoting localized therapeutic effects. Treated wounds exhibited near-complete re-epithelialization within 9 days, with increased angiogenesis and pericyte recruitment [33]. These effects were associated with a reduction in pro-inflammatory cytokines (IL-1β, IL-6, CXCL1) and MMP-9, while growth factors such as TGF-β1, IL-10, fibroblast growth factor 2, PDGF-BB, and VEGF-A were significantly upregulated [33].

Further supporting this approach, Perrault et al. [68] investigated topical anakinra in diabetic wounds, revealing improved histopathological outcomes, reduced wound area, and lower neutrophil infiltration after 21 days of treatment. The study hypothesized that IL-1Ra treatment reduces early inflammatory burden by limiting IL-1-mediated intercellular adhesion molecule expression, thereby decreasing neutrophil chemotaxis and macrophage phagocytic load. These findings emphasize the critical role of early inflammatory modulation in accelerating diabetic wound healing [68].

Role of TGF-β1 in diabetic wound healing

TGF-β1 is a multifunctional cytokine produced by platelets, macrophages, and epithelial cells, playing a key role in embryonic development, tissue regeneration, T-cell differentiation, and inflammatory modulation [69]. It also regulates osteoblast proliferation and contributes to fracture repair. In pathology, TGF-β1 has a dual role as a tumor suppressor in early carcinogenesis and a tumor promoter by enhancing metastasis through epithelial-mesenchymal transition (EMT) [70,71].

TGF-β1 signaling occurs via binding to type II receptors (TβRII), which recruit type I receptors (TβRI/ALK5). The canonical Smad pathway involves Smad2/3 phosphorylation, forming complexes with Smad4 to regulate gene transcription. Non-Smad pathways, including MAPK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), contribute to cell proliferation, survival, and fibrosis [72].

TGF-β1 modulates immune regulation, tissue repair, fibrosis, and cellular processes. It controls Th1/Th2/Th17 differentiation and enhances Tregs, maintaining immune tolerance [73]. It also suppresses excessive inflammation, particularly in autoimmune diseases, but paradoxically promotes Th17 differentiation, contributing to conditions like experimental autoimmune encephalomyelitis [73,74].

In wound healing, TGF-β1 stimulates collagen type I, fibronectin, and laminin synthesis via Smad2/3 activation, essential for ECM remodeling [74,75]. However, excessive activation leads to progressive fibrosis, mediated by lysyl oxidase cross-linking and plasminogen activator inhibitor-1 (PAI-1)-dependent ECM accumulation [74,75]. While it regulates inflammation resolution, an imbalance may result in maladaptive fibrosis [74,76].

TGF-β1 also governs cell proliferation, differentiation, apoptosis, and stem cell maintenance, supporting tissue homeostasis [77]. In the endocrine system, it inhibits aldosterone and steroidogenesis by downregulating Cyp11b2 and Cyp11b1 expression via Smad-independent pathways [78].

TGF-β1 is a central mediator of fibrosis, driving myofibroblast differentiation and ECM preservation in fibrotic diseases [79,80]. Canonical Smad3 signaling regulates collagen synthesis and fibrosis, while non-Smad pathways (MAPK/ERK and PI3K/Akt) mediate cellular survival and proliferation [80,81]. Connective tissue growth factor (CTGF) enhances TGF-β1 receptor binding, amplifying fibrotic signaling [80,82].

In fibrosis, TGF-β1 promotes α-SMA+ myofibroblast activation via Smad3, focal adhesion kinase, c-Jun N-terminal kinase, and PI3K/Akt pathways [80]. It stimulates collagen, fibronectin, and laminin synthesis, while suppressing ECM degradation via PAI-1 and tissue inhibitor of metalloproteinases-1, further reinforcing fibrotic progression [79,80]. TGF-β1 also enhances macrophage recruitment, increasing profibrotic cytokine production and modulating Tregs, which may exacerbate fibrosis in chronic disease [79,80].

TGF-β1’s fibrotic effects are evident in organ-specific diseases. In liver and kidney fibrosis, it induces collagen deposition and tubular EMT [80,81]. In airway remodeling, it promotes smooth muscle proliferation and mucus hypersecretion, contributing to asthma [83]. In bone metabolism, it regulates osteoblast differentiation and inhibits osteoclast function. In wound healing, TGF-β1 facilitates tissue repair, but persistent activation leads to chronic fibrosis [79,80].

TGF-β1 enhances collagen type I/III and fibronectin deposition, stimulates fibroblast proliferation, and promotes angiogenesis via VEGF upregulation, accelerating wound closure and reducing inflammation by limiting leukocyte infiltration [30,31,84,85]. It restores collagen fiber alignment and ECM organization, counteracting diabetic wound defects [31,85].

TGF-β1 signaling in diabetic wounds follows Smad and non-Smad pathways. Smad2/3 phosphorylation regulates collagen synthesis and fibroblast differentiation, with Smad6/7 providing negative feedback to prevent excessive fibrosis [31,85]. Non-Smad pathways (MAPK/ERK, PI3K/Akt) mediate rapid cellular responses, survival, and ECM deposition [84]. Zhao et al. [86] identified growth differentiation factor 10 as an inducer of the TGF-β1/Smad3 pathway in DFUs.

Animal studies support TGF-β1’s role in wound healing. El Gazaerly et al. [31] demonstrated that intravenous TGF-β1 administration for 14 days improved re-epithelialization, granulation tissue thickness, matrix density, and capillary formation in diabetic rats. However, human trials remain limited, with no randomized controlled trials testing TGF-β1 monotherapy. Instead, it is incorporated into platelet-rich plasma and growth factor cocktails [20,30,87].

Despite its promise, TGF-β1 therapy faces challenges. Systemic administration risks fibrosis, while high local concentrations may inhibit re-epithelialization by impairing keratinocyte motility [85]. Future research should focus on targeted delivery methods to maximize therapeutic benefits while minimizing fibrotic complications [30,31].

Interplay of PPARγ, IL-1β blocker, and TGF-β1 in DFU healing

The interplay between PPARγ, IL-1β, and TGF-β1 regulates key phases of diabetic wound healing by influencing macrophage polarization, inflammatory resolution, and tissue remodeling. Dysregulation of this axis, such as persistent IL-1β elevation with suppressed PPARγ and aberrant TGF-β1 signaling, leads to chronic inflammation, delayed fibroblast recruitment, and poor granulation tissue formation (Fig. 2). Understanding this cytokine network may open new therapeutic avenues in DFU management.

The molecular interaction between IL-1β and PPARγ plays a pivotal role in wound healing. IL-1β suppression restores PPARγ activity, enhancing TGF-β1-mediated tissue repair. A combination therapy of IL-1β blockers (e.g., anakinra, canakinumab), PPARγ agonists (e.g., rosiglitazone, pioglitazone), and TGF-β1 enhancers may synergistically target inflammation, ECM repair, and angiogenesis. Future studies should evaluate therapy efficacy by monitoring Smad3 phosphorylation or CTGF levels.

Conclusion

Healing diabetic wounds is a complex process driven by chronic inflammation, poor vascularization, and impaired tissue remodeling. PPARγ, IL-1β, and TGF-β1 are key regulators, with PPARγ reducing inflammation, IL-1β blockade breaking inflammatory cycles, and TGF-β1 balancing tissue repair without excessive fibrosis. These pathways also contribute to microvascular complications like diabetic retinopathy, where inflammation and angiogenic dysfunction play a role. While research supports their therapeutic potential, challenges remain in drug delivery, side effect management, and clinical translation. Combining molecular-targeted therapies with standard wound care may improve DFU management and benefit other diabetes-related complications.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Fig. 1.

Systemic factors contributing to chronic diabetic foot ulcers. Diabetic neuropathy leads to loss of protective sensation, vasculopathy impairs perfusion, and immune dysfunction increases infection risk—all fostering a non-healing wound environment.

Fig. 2.

Key molecular disruptions in diabetic wound healing. Interleukin-1 beta (IL-1β) promotes prolonged inflammation, while decreased peroxisome proliferator-activated receptor gamma (PPARγ) fails to counteract inflammatory signaling. Transforming growth factor beta 1 (TGF-β1) dysregulation contributes to impaired extracellular matrix (ECM) remodeling and delayed fibroblast activity.

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