IL-11 is a crucial determinant of cardiovascular fibrosis
TL;DR
Schafer et al. identified il-11 as a dominant TGF-β1-induced transcript in primary human cardiac fibroblasts and placed autocrine IL-11–IL11RA–ERK signaling downstream of multiple profibrotic stimuli. Recombinant or fibroblast-restricted IL-11 activated fibroblasts and caused cardiac/renal fibrosis in mice, while Il11ra1 loss reduced fibrosis in angiotensin-II, transverse-aortic-constriction and folate-nephropathy models. The paper established the mechanistic scaffold later extended to systemic and ovarian aging; it did not test aging or lifespan.
Design
- Paired primary human atrial fibroblasts from 84 patients were profiled by RNA sequencing after TGF-β1 stimulation (5 ng/ml, 24 h). Human cardiac and renal fibroblasts and mouse cardiac/renal fibroblasts were then perturbed with species-matched IL-11, IL-11/IL11RA blockade, IL11RA knockdown and MEK inhibitors.
- Recombinant mouse IL-11 (100 µg/kg subcutaneously each day for 21 days) and tamoxifen-inducible, fibroblast-restricted Il11 expression tested sufficiency in vivo. Recombinant mouse IL-11 was also given after myocardial infarction.
- Ten-to-twelve-week-old Il11ra1 knockout mice were compared with wild-type littermates in three loss-of-function models: male angiotensin-II infusion (2 mg/kg/day for 28 days), male transverse aortic constriction (2-week endpoint) and female folate nephropathy (180 mg/kg intraperitoneally; 28-day endpoint).
- Readouts included myofibroblast activation, extracellular-matrix protein production, hydroxyproline/collagen, signaling proteins, echocardiography, blood pressure and renal-injury markers. No statistical method was used to predetermine sample size, and the experiments were not randomized; treatment or genotype was concealed from investigators generating quantitative readouts.
Key findings
TGF-β1 increased IL11 RNA 8.5-fold in the 84-patient fibroblast cohort (DESeq2 adjusted P=6×10−218), and the change in IL11 correlated with fibroblast activation (ρ=0.47, adjusted P=6.44×10−6). IL-11 and IL11RA were both expressed by fibroblasts, supporting an autocrine loop. IL-11 promoted α-SMA-positive myofibroblast conversion and extracellular-matrix protein production largely through post-transcriptional, ERK-dependent mechanisms; IL-11 itself caused little change in the cardiac-fibroblast transcriptome. Recombinant human IL-11 was largely ineffective in mouse cardiac fibroblasts, whereas species-matched mouse IL-11 was active—an important constraint on interpreting earlier cross-species experiments.
In vivo recombinant or fibroblast-restricted IL-11 activated fibroblasts, increased cardiac and renal collagen and impaired organ function. In the loss-of-function experiments, Il11ra1 deletion reduced collagen and ERK activation after angiotensin II (wild-type control n=12, angiotensin II n=9; knockout control n=5, angiotensin II n=7), transverse aortic constriction (n=4–6/group) and folate injury (n=5–9/group). Blood-pressure telemetry after angiotensin II and pressure gradients after aortic constriction supported protection independent of reduced loading; the study did not directly show that genotype left the renal toxic injury itself unchanged.
Extrapolation to humans
| Dimension | Status | Notes |
|---|---|---|
| Pathway conserved in humans? | yes | TGF-β1→IL-11 and ERK-dependent fibroblast activation were tested in primary human cardiac and renal fibroblasts. |
| Phenotype conserved in humans? | partial | Human fibroblast activation and matrix production were measured ex vivo; organ fibrosis and dysfunction were tested in mice. |
| Replicated in humans? | no | No person received IL-11 or IL11RA inhibition. gap/needs-human-replication |
Interpretation and limits
The results support IL-11 as a downstream amplifier required for the tested TGF-β-linked fibrotic phenotypes, not as the sole cause of fibrosis across every organ or etiology. Most human evidence was ex vivo cell culture; causal organ-level experiments were in mice. In-vivo groups were generally small (often n=3–12), the single-cell heart experiment used one fibrotic and one control mouse per run and was repeated once, and several conclusions depend on convergent assays rather than one prespecified endpoint. The study did not evaluate chronic aging, late-life treatment, ovarian tissue or long-term blockade safety. The authors declared competing financial interests in the publication record.
Relevance to the requested papers
- widjaja-2024-il11-healthspan-lifespan extends the ERK-centered pathway to late-life systemic mouse phenotypes and survival.
- wu-2026-il11-ovarian-stiffness extends it to ovarian stromal fibroblasts, matrix stiffness and rodent reproductive aging.
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