Uncovering the Role of Exocrine Gland Fibrosis and Macrophage Polarization Imbalance in Chronic Sjögren's Syndrome
Background
Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by damage to exocrine glands such as the salivary and lacrimal glands. It is recognized as a representative intractable disease that significantly reduces patients' quality of life. Existing treatment approaches have remained limited to symptom relief, such as the administration of artificial tears or saliva-stimulating agents, due to the lack of fundamental therapies that can halt or reverse glandular fibrosis. As the disease progresses, irreversible fibrosis causes the exocrine gland tissue to harden progressively, leading to permanent loss of secretory function. Recent academic research has identified macrophages, innate immune cells, as a key factor in this tissue damage. Macrophages respond to signals from the surrounding microenvironment and differentiate into M1 subtypes that induce inflammation and M2 subtypes that promote tissue repair and fibrosis. It has been revealed that the imbalance in the polarization state of these macrophages plays a decisive role at each stage of SS progression. However, the specific spatiotemporal dynamics of cellular changes have not yet been clearly elucidated.
Key Findings
The research team clarified the spatiotemporal dynamics and functional transitions of M1 and M2 macrophage subtypes across the pathological stages of SS. In the early stage, the M1 subtype was found to dominate and lead the initial inflammatory damage. In the middle stage, the complex interaction between M1 and M2 subtypes was observed to sustain a chronic inflammatory state. In the late stage, abnormally differentiated M2 subtypes were identified as the main driver of fibrosis in exocrine glands. Behind this macrophage polarization imbalance, a multidimensional regulatory network was revealed, involving immune cell crosstalk, core signaling pathways, non-coding RNA epigenetic regulation, and immunometabolic reprogramming. The research team specifically uncovered the molecular mechanisms by which M2 macrophages stimulate exocrine gland cells to harden the tissue. Therapeutic potential was also confirmed. Traditional Chinese Medicine (TCM) compound prescriptions and single-component compounds were shown to be able to restore the disrupted immune balance by targeting key molecular nodes in macrophage polarization pathways.
Implications and Outlook
Several challenges remain before macrophage-targeted therapeutic strategies can be applied in clinical practice. The research team highlighted the need to develop tissue-specific delivery technologies to prevent drug effects on off-target tissues as a key challenge. Additionally, they emphasized the necessity of spatiotemporally tailored modulation, given that macrophage characteristics change with disease progression. Strategies that combine the strengths of traditional medicine and modern Western medicine are also emerging as viable alternatives. The use of specific biomarkers to diagnose the macrophage status of patients and administer personalized drugs through patient stratification techniques, along with securing early-window interventions before fibrosis becomes fully established, are expected to be key factors in improving treatment success rates. The research team anticipates that advanced tools such as single-cell multi-omics, spatial transcriptomics, gene editing, and organoid models will contribute to a more precise molecular-level understanding of macrophage heterogeneity. As research into visualizing intercellular communication within the glandular microenvironment advances, the development of precision autoimmune therapies with minimal side effects is expected to accelerate.
Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by damage to exocrine glands, and no effective treatment is currently available to reverse glandular fibrosis. As core effector cells of innate immunity, macrophages play a pivotal role in the dynamic imbalance of polarization states, which critically influences inflammation initiation, tissue injury, and irreversible fibrosis in SS. This review systematically delineates the heterogeneity of M1/M2 macrophage subsets, their spatiotemporal dynamics, and their functional transitions across different pathological stages of SS: M1 predominance drives early pro-inflammatory damage, M1/M2 interplay sustains chronic inflammation in the middle stage, and aberrant M2 polarization promotes late-stage glandular fibrosis. We further dissect the multi-level regulatory network underlying macrophage polarization imbalance, including immune cell crosstalk, core signaling pathways, non-coding RNA epigenetic regulation, and immunometabolic reprogramming. The in-depth mechanisms by which M2 macrophages drive the progression of glandular fibrosis are also summarized. In this context, we describe how certain traditional Chinese medicine (TCM) formulas and monomeric compounds can effectively restore the balance of macrophage polarization by targeting relevant pathways and molecular nodes. Moreover, we analyze the major bottlenecks currently hindering the clinical translation of macrophage-targeted strategies and propose innovative approaches, including tissue-specific delivery, spatiotemporally tailored modulation, integrated TCM-western medicine therapy, biomarker-guided patient stratification, and early-window intervention. Finally, we discuss the potential of cutting-edge technologies such as single-cell multi-omics, spatial transcriptomics, gene editing, and organoid models to decode the heterogeneity of macrophage subsets and their interactions with the microenvironment. Integration of these multidisciplinary
This research enables the establishment of concrete scenarios for implementing patient-tailored therapies in clinical settings. When a suspected patient visits, a salivary gland biopsy can be used to assess the distribution ratio of M1 and M2 macrophage subtypes. For patients in the early stage with prominent M1 activity, anti-inflammatory drugs can be prescribed to prevent glandular tissue destruction. Conversely, patients in the middle to late stages, where M2 subtypes dominate and fibrosis has already begun, can receive targeted therapies involving the local administration of specific compounds to the salivary glands. This approach aims to modulate the polarization of late-stage macrophages to prevent irreversible glandular transformation and preserve secretory function. In the pharmaceutical industry, co-culturing macrophages with salivary gland organoid models offers a valuable evaluation method. By implementing a system for rapid screening of large compound libraries, the time required to discover effective candidate compounds can be reduced by nearly half compared to conventional methods.