Age-related elevation of IL-21 levels may be a key driver of pulmonary dysfunction in the elderly, inducing pro-inflammatory states, cellular senescence, altered macrophage lipid metabolism, and impaired antiviral responses in the lungs.
Key Findings
Results
IL-21 induces a pro-inflammatory state in the lungs characterized by increased levels of key inflammatory cytokines.
Cytokines elevated following IL-21 exposure included TNF-α, IL-6, IL-33, CXCL-10, and IL-18.
Both murine models and human samples were used to demonstrate these pro-inflammatory changes.
The study used chronic IL-21 exposure as the experimental paradigm to assess pulmonary environment changes.
Results
IL-21 exposure promoted cellular senescence in the lungs, evidenced by upregulation of senescence-associated genes and increased frequencies of KLRG1-positive T cells.
Senescence-associated gene upregulation was observed following IL-21 treatment.
Increased frequencies of KLRG1-positive T cells were used as a marker of cellular senescence.
Both murine models and human samples were used to assess senescence markers.
Results
IL-21 treatment led to significant alterations in lung macrophage phenotype and function, including increased lipid accumulation.
Increased lipid accumulation in macrophages was observed following IL-21 exposure.
Upregulation of lipid uptake receptors TREM-2 and CD36 accompanied the lipid accumulation.
These changes in macrophage lipid metabolism were associated with elevated TGF-β secretion.
Elevated TGF-β secretion suggests a potential mechanism for IL-21-induced pulmonary fibrosis.
Results
IL-21 exposure resulted in impaired antiviral responses in the lungs.
Impaired antiviral responses were characterized by reduced MHC-II expression on macrophages.
Diminished IFN-α production in response to viral challenges was observed following IL-21 treatment.
These findings suggest IL-21 may compromise immune defense against respiratory viral infections.
Results
Aged mice exhibited a lung phenotype strikingly similar to that induced by IL-21 treatment in young mice.
The similar phenotype in aged mice included increased inflammation, cellular senescence, and altered macrophage lipid metabolism.
This parallel between aging and IL-21 treatment was observed using murine models.
The resemblance between aged mouse lungs and IL-21-treated young mouse lungs supports IL-21 as a driver of age-associated pulmonary changes.
Results
IL-21 expression was elevated in the lungs of Idiopathic Pulmonary Fibrosis (IPF) patients compared to controls.
Human IPF patient lung samples were compared to control samples for IL-21 expression levels.
Elevated IL-21 in IPF lungs supports the translational relevance of the murine findings.
This finding links IL-21 signaling to a clinically significant age-related pulmonary disease in humans.