---
title: "Smoldering Neuroinflammation in Progressive Multiple Sclerosis: Article Metadata and Missing Conte"
id: "frontiers-in-immunology-6-smoldering-neuroinflammation-in-progressive-multiple-sclerosis-mechanisms"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-smoldering-neuroinflammation-in-progressive-multiple-sclerosis-mechanisms"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901957"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Smoldering Neuroinflammation in Progressive Multiple Sclerosis: Article Metadata and Missing Conte
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-smoldering-neuroinflammation-in-progressive-multiple-sclerosis-mechanisms
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901957)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided contains only website navigation and metadata links from Frontiers in Immunology; the full article text and substantive content were not included in the source provided. - The original article title supplied by the user is “Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities,” and the journal named is Frontiers in Immunology. The article URL was supplied but the body text was not present in the source. - Because the source text did not include the article abstract, introduction, methods, results, discussion, figures, tables, or conclusions, no article-specific data, mechanistic descriptions, imaging findings, biomarker details, or therapeutic recommendations can be extracted or summarized from the provided material. - Key topic terms implied by the title include **progressive multiple sclerosis**, **neuroinflammation**, **imaging biomarkers**, and **therapeutic opportunities**, but the source did not report definitions, mechanisms, biomarker names, imaging modalities, or therapeutic strategies related to these terms. - Relevant article-level details that were present in the source: navigation links, journal sections list (including a section for Multiple Sclerosis and Neuroimmunology), and general Frontiers site menus. These do not provide clinical content about the article’s findings. - Because the article body is absent, any clinical interpretations, recommendations, or specific study results cannot be generated without accessing the full article. The source-only fact is that the full text was not included in the provided material. - Recommended next steps (source-driven): retrieve the full article text from the supplied URL or the journal platform to obtain the complete manuscript, including abstract, methods, data, and conclusions necessary for clinical synthesis.
## Clinical Analysis & Structured Key Points
Frontiers | Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities REVIEW article Front. Immunol. , 02 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901957 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Editor & Reviewers Edited by S B Shairaz Baksh Reviewed by J B Jianfeng Bao A E Ahmed Elkady A J Abdul Jaber Tayem 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 Table 1 Evidence hierarchy supporting chronic active lesions as substrates of smoldering progression in multiple sclerosis. View in article Table 2 Cellular and molecular architecture of chronic active lesions in progressive multiple sclerosis. View in article Table 3 In vivo imaging biomarkers of smoldering neuroinflammation in progressive multiple sclerosis. View in article Table 4 Clinical consequences and therapeutic implications of chronic active lesions in progressive multiple sclerosis. View in article REVIEW article Front. Immunol. , 02 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901957 Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities M W Min Wang B Z Bo-chi Zhu X M Xijing Mao * Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China Article metrics View details Abstract Progressive multiple sclerosis (MS) remains a major therapeutic challenge because disability often continues to accumulate despite effective control of relapses and new focal inflammatory lesions. This dissociation suggests that progression is driven not only by acute inflammation, but also by a distinct process increasingly termed smoldering neuroinflammation. Recent evidence supports chronic active lesions as an important but non-exclusive pathological substrate of this process. These lesions are characterized by persistent lesion-edge inflammation, slowly expanding tissue injury, iron-laden myeloid cells, astrocyte–immune crosstalk, and incomplete repair. Importantly, this inflammatory activity is not restricted to isolated white matter plaques, but is spatially compartmentalized across the central nervous system, involving interactions among white matter lesions, meninges, cortex, and subcortical regions. Advances in susceptibility-based MRI and PET imaging now allow in vivo assessment of imaging-related correlates of this otherwise hidden pathology, including paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and TSPO-PET-defined inflammatory activity. Although these biomarkers overlap only partially, they provide complementary insights into lesion composition, structural expansion, and metabolic inflammation. Accumulating studies further suggest that current disease-modifying therapies incompletely control established chronic lesion biology, while other inflammatory-independent or age-related neurodegenerative processes may also contribute to progression. In this review, we discuss the pathological basis, imaging correlates, and therapeutic implications of smoldering neuroinflammation in progressive MS. Highlights Smoldering neuroinflammation is a major contributor to progression in MS. PRLs, SELs, and TSPO-PET reveal chronic active lesions in vivo . Future therapy must target lesion-edge and CNS-trapped inflammation. 1 Introduction Multiple sclerosis (MS) has traditionally been conceptualized as an autoimmune demyelinating disease driven by episodic inflammatory relapses, blood–brain barrier disruption, and new focal inflammatory lesions ( 1 – 3 ). This model has supported major therapeutic advances, particularly through disease-modifying therapies that reduce relapse frequency and conventional MRI activity. However, it does not fully explain a key clinical problem in progressive MS: disability can continue to accumulate despite apparent control of relapses and new gadolinium-enhancing lesions ( 4 – 6 ). This dissociation suggests that progression is not merely residual relapse-associated inflammation, but may reflect a chronic, compartmentalized pathological process that remains insufficiently captured by conventional clinical and imaging measures. Recent pathological, molecular, and imaging studies have identified smoldering neuroinflammation and chronic active lesions as central substrates of progressive MS ( 7 – 9 ). These lesions are characterized by persistent lesion-edge inflammation, resident myeloid activation, astrocyte–immune crosstalk, iron accumulation, slow tissue expansion, and incomplete repair ( 10 – 12 ). In parallel, susceptibility-based MRI and PET imaging have enabled in vivo assessment of this otherwise hidden pathology through paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and TSPO-PET-defined inflammatory activity. However, existing reviews have often discussed chronic active lesions, imaging biomarkers, or progressive MS therapeutics as relatively separate topics. Less attention has been given to how PRLs, SELs, and TSPO-PET provide complementary rather than interchangeable information, and to whether chronic active lesion burden can be linked to treatment response or therapeutic failure. Therefore, this review aims to integrate three related but incompletely connected areas of the field. First, we summarize the lesion-edge cellular and molecular architecture that sustains smoldering neuroinflammation in progressive MS. Second, we compare PRLs, SELs, and TSPO-PET as complementary imaging windows onto chronic active lesion biology, emphasizing their partial overlap, distinct pathological meanings, and translational limitations ( 13 – 15 ). Third, we discuss how chronic active lesions may inform therapeutic response, treatment resistance, patient stratification, and progression-focused trial design. By linking pathology, multimodal imaging, and therapeutic implications, this review seeks to clarify why smoldering neuroinflammation is not only a mechanistic concept, but also a clinically relevant framework for monitoring and treating progressive MS. This review includes several categories of evidence: neuropathological and lesion-level molecular studies, susceptibility-based MRI studies, longitudinal SEL analyses, PET studies of innate immune activation, clinical prognostic studies, and treatment-related imaging studies. General reviews and studies of relapse-associated inflammation or conventional DMT mechanisms were used primarily as background. The core conclusions of this review are supported mainly by studies directly addressing chronic active lesions, PRLs, SELs, TSPO-PET-defined inflammatory activity, clinical progression, and treatment-related changes in chronic lesion biomarkers. Throughout the review, we distinguish relatively direct pathological evidence from imaging-related correlates and from more speculative therapeutic implications. 2 From relapse-associated inflammation to smoldering progression in MS The classical inflammatory model of MS is rooted in the biology of relapses: acute focal immune infiltration, formation of new inflammatory lesions, transient blood–brain barrier opening, and periods of partial clinical recovery ( 16 , 17 ). This model remains highly relevant, particularly for relapsing forms of the disease, and it explains why therapies targeting adaptive immunity can substantially reduce relapse frequency and new MRI activity. Yet it is increasingly clear that this framework cannot fully account for the biology of progressive disability accumulation. In many patients, especially those with secondary progressive or primary progressive MS, worsening neurological impairment continues despite relative suppression of overt relapse-associated inflammation ( 18 – 20 ). This phenomenon indicates that progression reflects not merely a reduction in inflammatory intensity, but a transition to a different inflammatory mode—one that is more chronic, spatially restricted, and closely coupled to irreversible tissue injury. 2.1 Why progression persists beyond relapses One of the central challenges in MS research is explaining why disability progression can continue in patients who appear clinically and radiologically stable by conventional measures. Relapses represent only the most visible component of inflammatory disease activity. By contrast, progressive worsening seems to depend more strongly on persistent low-grade inflammation within established lesions, chronic glial activation, and cumulative neuroaxonal damage. In this setting, tissue injury unfolds over months to years rather than days to weeks, making it less conspicuous clinically but potentially more consequential for long-term neurological decline ( 21 – 24 ). This idea is supported by molecular and imaging evidence showing that chronic lesion activity remains present even in non-acute phases of disease. Jäckle et al. provided a particularly important contribution by demonstrating that slowly expanding lesions in progressive MS have a distinct molecular signature enriched at the lesion rim, with preferential accumulation of resident microglia/macrophage-associated inflammatory programs rather than a pattern dominated by acute peripheral immune infiltration ( 25 ). These findings suggest that progression is sustained by lesion-edge processes that persist after the initial lesion-forming event. Absinta et al. extended this concept by revealing a cellular axis involving lymphocytes, microglia, and astrocytes within chronic active lesions, thereby showing that ongoing tissue damage reflects a coordinated inflammatory microenvironment rather than isolated glial activation. Together, these studies argue that the pathological basis of progression lies in a CNS-trapped inflammatory architecture that is at least partially autonomous from classical relapse biology. Further support for this view comes from biomarker studies linking chronic lesion activity to neuroaxonal injury. Maggi et al. reported that chronic white matter inflammation, as detected by paramagnetic rim pathology on MRI, was associated with increased serum neurofilament light chain (sNfL) levels and greater disease severity in non-acute MS ( 26 ). This is an important observation because it bridges lesion-level inflammatory persistence with a systemic biomarker of axonal damage, strengthening the argument that smoldering inflammation is not merely a radiological curiosity but an active driver of neurodegeneration. More recent work has also reinforced the clinical relevance of chronic active lesions at the patient level. Bagnato et al. found that chronic active lesion burden is frequently associated with disease progression and disability accumulation, further supporting the view that these lesions are not incidental findings but rather key indicators of a progression-prone disease state ( 27 ). Taken together, these findings support a conceptual shift: progression beyond relapses should not be interpreted as evidence of inflammatory exhaustion, but as evidence of inflammatory transformation. The dominant biology moves from acute focal lesion formation driven largely by peripheral immune entry to a more compartmentalized process characterized by persistent innate immune activation, chronic lesion-edge inflammation, and cumulative neuroaxonal loss. This distinction has major implications for both disease monitoring and therapeutic strategy, because it suggests that relapse suppression alone is unlikely to fully prevent progression unless the underlying smoldering pathology is also addressed. 2.2 Smoldering lesions as the pathological substrate of progression Chronic active lesions are increasingly recognized as one of the most important pathological substrates linking inflammation to progression in MS. Unlike inactive scars, these lesions remain biologically active at their edges, where inflammatory cells, especially microglia and macrophage-lineage cells, form a rim surrounding a relatively hypocellular demyelinated core ( 28 – 30 ). This rim is not a static boundary. Rather, it reflects a zone of ongoing myelin breakdown, incomplete debris clearance, oxidative stress, and axonal injury. Over time, such lesions can expand slowly, leading to progressive tissue destruction and failure of repair. The concept of the slowly expanding lesion captures this process particularly well and provides a mechanistic explanation for how chronic inflammatory activity can persist long after the acute phase of lesion formation has subsided. The biological significance of these lesions lies not only in their persistence, but also in the type of injury they promote. Chronic active lesions are associated with sustained demyelination, axonal transection, mitochondrial stress, and remyelination failure, all of which contribute to gradual but irreversible functional decline. Because this damage accumulates at the lesion border, it is often poorly captured by conventional MRI measures focused on new lesion counts or gadolinium enhancement ( 31 – 33 ). In this sense, chronic active lesions represent a form of “hidden activity” that is especially relevant to progression independent of relapse activity (PIRA). They provide a pathological framework for understanding why patients may worsen despite the apparent absence of new inflammatory events by standard criteria. Imaging and clinical studies increasingly support the role of smoldering lesions as progression-driving structures in vivo ( 34 – 38 ). Maggi et al. linked chronic white matter inflammation to higher sNfL levels, implying that these lesions contribute to continuous axonal injury even outside acute relapse periods ( 26 ). Bagnato et al. further associated chronic active lesion burden with disability accumulation and clinical progression, reinforcing their importance as markers of disease severity ( 27 ). These observations are particularly relevant in the context of PIRA, which is now recognized as a major component of long-term disability accrual in MS. Smoldering lesions offer a biologically plausible substrate for PIRA because they integrate persistent inflammation, ongoing tissue damage, and inadequate repair within a single lesion-centered framework. Accordingly, progressive MS should not be viewed simply as a stage in which inflammation fades and neurodegeneration takes over. Rather, it is better understood as a state in which inflammatory injury becomes chronic, compartmentalized, and structurally embedded within established lesions. Smoldering lesions thus occupy a central position at the interface between inflammation and neurodegeneration: they are inflammatory enough to drive ongoing tissue destruction, yet chronic enough to evade traditional definitions of active disease. Recognizing these lesions as a core pathological substrate of progression is therefore essential for rethinking both how progressive MS is monitored and how next-generation therapies should be designed. Because the concept of chronic active lesions is supported by heterogeneous lines of evidence, it is important to distinguish pathological validation from imaging correlates, clinical prognostic associations, and treatment-response data. These evidence types do not carry the same inferential weight. Neuropathological and lesion-level molecular studies provide relatively direct validation of chronic active lesion biology, whereas longitudinal MRI and PET studies provide in vivo correlates of lesion persistence, expansion, and inflammatory metabolism ( 39 , 40 ). Clinical outcome studies further support the prognostic relevance of chronic active lesions, but causal links to disability accumulation and therapeutic response remain incompletely established. Table 1 summarizes this evidence hierarchy and distinguishes relatively stable conclusions from more speculative or emerging interpretations. Figure 1 illustrates the transition from acute relapse-associated inflammation to smoldering progression in multiple sclerosis. It highlights chronic active lesions as the pathological substrate linking CNS-compartmentalized inflammation to persistent tissue injury, neuroaxonal loss, and progression independent of relapse activity. Table 1 Evidence category Representative studies/evidence Main conclusion supported Strength of conclusion Remaining uncertainty Representative PMID Neuropathological validation Post-mortem and lesion-level studies showing hypocellular demyelinated cores, inflammatory rims, and persistent lesion-edge activity Chronic active lesions are real pathological entities rather than imaging artifacts Relatively stable Degree of heterogeneity among lesion subtypes remains incompletely defined 32577755 Lesion-edge molecular profiling Jäckle et al. identified molecular signatures of slowly expanding lesions enriched at lesion borders Slowly expanding lesions have distinct inflammatory programs at the rim Relatively stable Whether all SELs represent the same pathological stage remains uncertain 32577755 Multicellular lesion biology Absinta et al. described a lymphocyte–microglia–astrocyte axis in chronic active MS lesions Chronic lesion persistence reflects a multicellular inflammatory niche Relatively stable The relative contribution of each cell type may vary across patients and disease stages 34497421 Iron-related pathological validation Hofmann et al. linked myeloid iron uptake pathways with paramagnetic rim formation Iron-laden myeloid cells provide a pathological basis for PRLs Relatively stable Iron accumulation may not capture all forms of chronic lesion activity 37715818 Longitudinal PRL imaging Dal-Bianco et al. and Reeves et al. showed long-term evolution and prognostic relevance of iron rim lesions PRLs can persist over time and are associated with more aggressive disease evolution Moderately stable Imaging protocols and field strength influence PRL detection 33484118; 40357663 Longitudinal SEL imaging Elliott et al. and Calvi et al. linked slowly expanding lesions with chronic lesion expansion and disability in SPMS SELs capture structural lesion expansion over time Moderately stable SEL definitions and segmentation pipelines vary across studies 35277438 PRL–SEL correspondence Elliott et al. showed only partial lesion-level overlap between PRLs and SELs PRLs and SELs are complementary rather than interchangeable biomarkers Relatively stable The biological meaning of PRL-only and SEL-only lesions requires further validation 37036134 PET evidence Hamzaoui et al. and Polvinen et al. showed TSPO-PET-detectable chronic inflammatory activity associated with progression PET provides evidence that chronic lesions can remain metabolically inflammatory in vivo Moderately stable TSPO specificity, accessibility, and clinical standardization remain limitations 37039158 Clinical prognostic studies Studies linking PRL/SEL/chronic lesion burden with sNfL, atrophy, disability, or progression Chronic active lesion burden is clinically relevant and may predict worse outcomes Moderately stable Association does not fully prove causality 34088875; 40357663 Treatment-response studies Maggi et al. showed B-cell depletion does not resolve chronic active lesions; Zinger et al. reported partial reduction of inflammation with dimethyl fumarate Current DMTs may incompletely control chronic lesion biology Emerging/partly speculative Treatment-response evidence remains limited and requires prospective validation 37437310; 35046083 Trial enrichment and therapeutic targeting Imaging biomarkers proposed for stratification and progression-focused endpoints PRLs, SELs, and TSPO-PET may help select patients and monitor lesion-directed therapies Speculative/emerging Clinical utility as validated trial endpoints remains to be proven 37349108 Evidence hierarchy supporting chronic active lesions a
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