IFN-γ as a Self-Sustaining Amplifier of Dystrophic Muscle Inflammation, With Fibrosis Still One Step Removed

Question: How does IFN-γ signaling drive chronic macrophage-mediated inflammation and fibrosis in skeletal muscle regeneration and dystrophic myopathies?

Answer

Taken together, the retrieved papers support IFN-γ as a disease-specific, self-reinforcing circuit rather than a generic marker of muscle inflammation: it is the dominant interferon program in at least one muscular dystrophy, it converges on macrophage JAK1/2–STAT1 signaling, and it is sustained by continuing cytokine exposure rather than by fixed epigenetic memory, which is why it can be interrupted pharmacologically. Across these papers, however, the causal chain from IFN-γ to fibrosis is only partly assembled: IFN-γ is repeatedly positioned upstream of non-resolving macrophage activation and of muscle-intrinsic regenerative failure, while the actual matrix effectors — FAP-derived collagen VI, TGF-β1, TIMP1 — have been shown to impair myogenesis directly but have not been connected to IFN-γ in skeletal muscle in the retrieved literature. The defensible position is therefore that IFN-γ drives the chronicity of macrophage-mediated inflammation in dystrophic muscle, with fibrosis a strongly inferred but not yet demonstrated downstream consequence.

IFN-γ dominance is a disease-specific innate state, not a readout of generic interferon activation

In FSHD, DUX4 induces a viral-mimicry-like pathway that is fundamentally uncoupled from canonical type I IFN and instead establishes a non-canonical innate state dominated by IFN-γ signaling, which the authors propose explains the non-resolving inflammation characteristic of the disease [6]. In that same study, IFN-γ treatment alone was sufficient to recapitulate key DUX4 pathogenic effects, and IFN-γ inhibition rescued muscle inflammation and halted disease progression in FSHD models [6]. This is the strongest causal evidence in the retrieved set, and it is specifically type II, not type I, interferon.

Human myositis biopsies show the same skew but with disease-specific wiring: IBM had the largest number of differentially overexpressed cytokine genes, including IFNG, CXCL9, CXCR3, CCL5 and CCR5, anti-Jo1 and anti-PM/Scl patients shared a similar type 1 profile, dermatomyositis patients overexpressed a different type 1 set, and IMNM showed no predominant inflammatory pattern [18]. Local immunoglobulin gene expression in myositis correlated strongly with disease activity and was robustly associated with IFN-γ signaling, and clustering on immunoglobulin genes alone separated controls from antisynthetase syndrome and IBM patients [14].

The type I/type II split is not clean across diseases: dermatomyositis is described as driven by overactivation of both type I and II interferons, and TYK2/JAK1 inhibition suppressed interferon-responsive pathways with clinical improvement [12]. In treatment-naive juvenile dermatomyositis, a 15-gene interferon signature was elevated in muscle and in macrophage-enriched regions and correlated with clinical weakness [10], and single-nucleus profiling localized an interferon response signature across endothelial, stromal and immune compartments [13]. In LGMD2F, Sgcd-/- muscle showed innate immune overactivation that was suppressed, together with NF-κB2 and interferon-stimulated genes, by (-)-epicatechin [19].

Macrophages are both source and STAT1-addressed target of the loop

Spatial transcriptomics of IBM muscle identified immune hubs in which interferon-responsive CD8+ T cells and interferon-stimulated antigen-presenting macrophages organized around myofibers, with myofibers inside those niches upregulating interferon-responsive genes plus HLA class I and II machinery [23]. That architecture places the IFN-γ–responding macrophage in direct physical contact with the fiber it is remodeling, rather than in a diffuse inflammatory infiltrate.

STAT1 is the convergent node linking this macrophage state to failed myogenesis: age-dependent dysferlin accumulation in macrophages induces an M1 phenotype, activates STAT1 via calcium influx, and renders those macrophages capable of inhibiting myoblast differentiation in co-culture [16]. IFN-γ classically signals through JAK1/2-mediated STAT1 homodimers in macrophages [9], so this STAT1-dependent block is the plausible effector arm of the IFN-γ circuit. The pathway is not purely STAT1, however: IFN-γ also rapidly and directly activates STAT3 through JAK1 and JAK2, STAT3 forms heterodimers with STAT1 and is co-recruited to a subset of STAT1-bound regulatory elements, though STAT1 can substitute when STAT3 is absent, indicating a limited regulatory contribution [9].

Macrophage-derived paracrine signals engage JAK/STAT in the stromal compartment directly: in tendon fibroblasts, the transcriptional response to M1 macrophage-conditioned medium required both NF-κB and JAK/STAT, with each pathway driving distinct downstream outputs [8]. The crosstalk is bidirectional and not simply proportional to macrophage burden — FAP-specific loss of autocrine IGF-I increased macrophage accumulation while reducing ECM output [2].

The primed state depends on continued cytokine exposure, so the loop is interruptible

Durable IFN-γ-induced enhancers in human macrophages persist for days after washout, but the persistence is not cell-intrinsic: JAK/STAT signaling continues after cytokine removal, and blocking IFN-γ signaling with a JAK inhibitor or anti-IFN-γ neutralizing antibodies reverses the enhancers and erases the potentiated state [22]. Chronic IFN-γ-driven inflammation is therefore a maintained signal, not a locked-in differentiation state, which is the mechanistic justification for treating established dystrophic inflammation rather than only preventing it.

The pathway's own brake is IFN-γ-inducible: SOCS1 blocks JAK kinase activity to restrain JAK-STAT signaling, and ARAP2 binds the SOCS1 SH2 domain through tyrosine 415 to limit SOCS1's inhibitory capacity, thereby promoting the IFN-γ response [11]. Which JAK to hit matters: in AIRE deficiency, selective JAK1 and JAK2 inhibition suppressed IFN-γ signaling and tissue injury with JAK2 giving the most robust protection, whereas JAK3 inhibition reduced T cell accumulation but paradoxically increased the proportion of IFN-γ-producing T cells without attenuating IFN-γ-driven inflammation [17]. This non-muscle evidence argues that lymphocyte depletion is not equivalent to IFN-γ axis blockade.

Fibrosis is executed by FAP-derived matrix effectors that have not yet been tied to IFN-γ in muscle

Collagen VI is a conserved pro-fibrotic ECM component across DMD, OPMD and IBM; FAPs are its predominant source, patient-derived FAP xenotransplantation caused collagen deposition, myofiber atrophy and Pax7+ stem cell depletion, and FAP-derived collagen VI was sufficient to impair myogenic fusion while COL6 silencing restored fusion capacity [1]. This establishes a direct matrix-to-myogenesis axis that does not require an immune intermediate to explain regeneration failure.

In volumetric muscle loss, a β1-integrin-high FAP subpopulation with increased fibrotic gene expression and myofibroblast potential secreted TGF-β1 and TIMP1, producing both pro-fibrotic and anti-myogenic signaling [3]. In a DMD rat model, EP4 agonism dose-dependently inhibited FAP differentiation into α-SMA myofibroblasts, resolved established fibrosis below pre-treatment baseline, and re-activated a regenerative program restoring the myofiber pool [20]. Fibrosis in dystrophic muscle is thus reversible at the level of FAP differentiation, but none of these papers test whether IFN-γ is the upstream signal that licenses that differentiation.

IFN-γ also acts cell-intrinsically on striated muscle, decoupling inflammation from regenerative failure

Systemic IFN-γ overexpression produced a myocardial IFN-γ response signature with downregulation of oxidative phosphorylation and fatty acid oxidation, decreased mitochondrial oxygen consumption, and a glycolytic shift, all abrogated by cardiomyocyte-specific IFNGR deletion [15]. This demonstrates direct IFNGR-dependent reprogramming of striated muscle cells by IFN-γ, independent of immune recruitment.

Whether such muscle-intrinsic damage is IFN-γ-dependent in dystrophy remains contested. In juvenile dermatomyositis, the interferon signature correlated with weakness but mitochondrial dysregulation was present regardless of interferon activity or muscle strength [10]. In DMD, satellite cells show intrinsic differentiation stalling, senescence and autophagy defects attributable to dystrophin loss rather than to an inflammatory signal, and autophagy induction rescued differentiation [7]. A separate DMD amplifier is humoral rather than IFN-γ-mediated: early sarcolemmal IgG accumulation from ectopic FcγR1 on dystrophin-deficient myofibers exacerbated tissue inflammation, and B cell depletion provided sustained benefit in two murine models [5].

Conflicts and gaps

The largest conflict is type I versus type II interferon primacy. FSHD is explicitly uncoupled from type I IFN and IFN-γ-dominated [6], whereas dermatomyositis is described as type I and II co-driven [12] and JDM carries a strong type I-associated signature [24]. Worse for a simple model, high and sustained type I IFN can cell-intrinsically impair IFN-γ responsiveness in infected macrophages [21], meaning an IFN-γ signature may sometimes mark failed rather than dominant type I signaling.

The central gap is DMD: none of the retrieved DMD papers tests IFN-γ or IFNGR directly. The DMD evidence is instead sarcolemmal IgG/FcγR1 [5], FAP-derived collagen VI [1], and satellite cell-intrinsic defects [7]. A second gap is cellular source: the retrieved papers show interferon-responsive CD8+ T cells and macrophages co-localized in IBM [23] but do not establish whether macrophages are the principal IFN-γ producers in dystrophic muscle. A third gap is that no retrieved study deletes IFNGR or JAK1 in FAPs or myofibers in a dystrophy model, so whether IFN-γ acts on the fibrotic progenitor or only on the immune compartment is untested. Finally, the ordering of IFN-γ versus TGF-β is unresolved: fibrosis is repeatedly attributed to TGF-β/SETDB1 [4] and TGF-β1/TIMP1 [3] without reference to IFN-γ.

What would change the answer

A conditional deletion of Ifngr1 or Jak1 in Pdgfra-lineage FAPs versus LysM-lineage macrophages in mdx and D2-mdx mice, with fibrosis quantified by hydroxyproline and collagen VI deposition and regeneration by eMHC fiber counts, would establish or refute the FAP-as-IFN-γ-target step. Paired single-cell and spatial transcriptomics of human DMD, FSHD and IBM biopsies with ligand-receptor inference for IFNG–IFNGR1 and measurement of both type I and type II modules in the same tissue would resolve the primacy conflict. A human iPSC-derived macrophage–FAP–myoblast tri-culture with IFN-γ stimulation and IFNGR1 or JAK1 knockdown would test sufficiency and directionality in a human genetic background. Clinically, the decisive experiment is an anti-IFN-γ or JAK2-selective trial in FSHD with paired muscle biopsy transcriptomics and histology, extending the FSHD model result [6] to human tissue and testing whether the reversibility seen in macrophage enhancer assays [22] translates into fibrosis resolution.

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How this survey was made

This survey answers one question: “How does IFN-gamma signaling drive chronic macrophage-mediated inflammation and fibrosis in skeletal muscle regeneration and dystrophic myopathies?”

We keep our own collection of recent preprints and refresh it every day from bioRxiv, medRxiv, arXiv, PsyArXiv, SocArXiv and ChemRxiv. For each survey, we search that collection for recent work and keep the strongest matches: papers that use the same terms as the question, and papers on the same topic in different words.

The text was written from the titles and abstracts of those papers; the full texts were not read. Statements that draw on a particular paper are marked with a number in brackets. The reference list just above is the 24 papers whose work this text draws on, chosen from the 110 papers those searches returned; the rest of the shortlist is not printed. It is not a complete review of everything published on the question.

Treat this as a starting point and a reading list, not a peer-reviewed review. The searches behind this survey ran on October 22, 2026 and covered work from the previous two years.