Key result
ICOS or ICOSL blockade alongside Ang-II increases mortality to ~45% and worsens systolic dysfunction in mice.
Why the study?
The contribution of Inducible T-cell Co-Stimulator (ICOS) and its Ligand (ICOSL) signalling to cardiac injury, remodelling, and fibrosis under experimental pressure overload remained undefined.
Does ICOS or ICOSL blockade modulate cardiac remodelling and fibrosis in mice with experimental Angiotensin II-induced pressure overload?
Does ICOS or ICOSL blockade modulate cardiac remodelling and fibrosis in mice with experimental Angiotensin II-induced pressure overload?
In a murine model of Angiotensin II-induced pressure overload, blocking ICOS or ICOSL immune checkpoint pathways increased mortality and worsened systolic dysfunction, with ICOSL inhibition specifically accelerating myocardial fibrosis and adverse remodelling.
Checkpoint inhibition warrants caution in heart failure; leaves open distinct ICOS versus ICOSL remodeling effects.
Introduction Cardiac fibroblasts are essential for myocardial repair after injury; however, their overactivation leads to maladaptive fibrosis and progression to heart failure. The Inducible T-cell Co-Stimulator (ICOS) and its Ligand (ICOSL) have emerging roles beyond adaptive immunity, but their contribution to cardiac injury and remodelling remains undefined. Understanding ICOS-ICOSL signalling in the injured myocardium may reveal novel mechanisms regulating fibroblast activation and fibrotic progression. Purpose To investigate the role of ICOS-ICOSL signalling in cardiac remodelling and fibrosis in experimental pressure overload. Methods Six-month-old male Balb/C mice underwent osmotic mini-pump implantation to receive Angiotensin II (Ang-II; 1.5 mg/kg/day) or saline for 15 days. ICOS or ICOSL signalling was inhibited with monoclonal antibodies (150 µg/dose i.p., every 3 days). Mice were allocated to six groups: Veh/Isotype (n=6), AngII/Isotype (n=16), Veh/anti-ICOS (n=7), AngII/anti-ICOS (n=16), Veh/anti-ICOSL (n=7), and AngII/anti-ICOSL (n=16). Cardiac morpho-functional changes were assessed by echocardiography. Myocardial remodelling and fibrosis were evaluated using histological analysis and qRT-PCR. Results Combined Ang-II and ICOS or ICOSL inhibition significantly increased mortality (40-50%), compared with Ang-II alone (13%). Both treatments, when combined with Ang-II, aggravated systolic dysfunction, reducing ejection fraction (EF) and fractional shortening compared to controls. Notably, ICOSL blockade worsened cardiac remodelling, increasing relative wall thickness and left ventricular remodelling index, and reduced EF even as a monotherapy. Myocardial fibrosis was increased in AngII/Isotype and further exacerbated in AngII/anti-ICOSL mice, accompanied by elevated CTGF mRNA expression level. TGF-β and Col1a1 expression were significantly upregulated only following ICOSL inhibition. Differential collagen regulation was observed; ICOS blockade increased Col3a1 expression, whereas ICOSL inhibition increased Col1a1 expression and the Col1a1/Col3a1 ratio, indicating a shift toward a stiffer extracellular matrix phenotype. The Ang-II-induced reduction in the Myh6/Myh7 ratio (hypertrophy marker) was attenuated by ICOS blockade but worsened by ICOSL inhibition. Consistently, NPPB expression and circulating NT-proBNP levels were normalised with ICOS inhibition but remained elevated with ICOSL blockade. Conclusions ICOS-ICOSL signalling critically modulates cardiac remodelling under Ang-II-induced stress. ICOS inhibition partially mitigates hypertrophic and fibrotic responses, whereas ICOSL blockade accelerates adverse remodelling, matrix stiffening, and functional decline. These findings identify immune co-stimulatory signalling as a regulator of fibroblast-driven cardiac pathology and highlight the therapeutic potential and risk of targeting this pathway in heart failure.
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Hegedus et al. (2026) studied Experimental cardiac fibrosis and remodelling (Angiotensin II-induced pressure overload) (n=68). Anti-ICOS or anti-ICOSL monoclonal antibodies vs. Isotype control (with Angiotensin II 1.5 mg/kg/day or saline) was evaluated on Mortality, systolic function, and myocardial remodelling/fibrosis. Combined Ang-II and ICOS or ICOSL blockade significantly increased mortality (40-50% vs 13% with Ang-II alone) and aggravated systolic dysfunction in mice.
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