Biology subjects

Suarez, M. F.

Publications and source records attributed to Suarez, M. F..

4 recordsLinked to original sources

bioRxiv2026

Molecular profiling implicates immune-driven adaptive homeostasis in maintaining intraocular pressure with age

Aging and ocular hypertension are primary risk factors for glaucoma - a major cause of blindness worldwide. Ocular hypertension results from dysfunction in the outflow tissues - the trabecular meshwork (TM) and Schlemm's canal (SC), which are key regulators of intraocular pressure (IOP) homeostasis. Despite lifelong multifaceted stress to the outflow pathway, ocular hypertension sufficient to develop glaucoma occurs in only a minority of individuals. The mechanisms that preserve physiological IOP with aging in most individuals remain poorly understood. Using single-cell RNA sequencing and protein validation in mouse outflow tissues, we found that aging is accompanied by subtype-specific changes in TM cells, including altered extracellular matrix maintenance, reduced trophic signaling to SC, and increased profibrotic signaling. Coincident with these changes, we observed age-dependent immune remodeling, marked by increased macrophage abundance in outflow tissues. Our model predicts that macrophages maintain SC homeostasis via VEGFA signaling - normally supplied by the TM and required for normal SC function, but impaired with age. This pattern supports a paradigm in which adaptive immune remodeling contributes to preserving IOP homeostasis despite progressive aging-associated cellular dysfunction. More broadly, we identify the TM/SC outflow pathway as a model for understanding how aging tissues preserve physiological function through coordinated structural, trophic, and adaptive immune remodeling.

cell biology↗

bioRxiv2025

Intracameral Puncture Lowers Intraocular Pressure and Triggers an Immune Response in the Conventional Outflow Tract

PurposeIntracameral injection is an effective delivery method for biomedical agents and therapeutics to conventional outflow tract tissues. However, the effect of intracameral injections on intraocular pressure and aqueous dynamics has not been well characterized, warranting further investigation. MethodsWild type 3-5-month-old C57BL/6 mice were subjected to intracameral puncture (ICP, without injection of any material). Following ICP, intraocular pressure (IOP), outflow facility, aqueous production, episcleral vessel diameter, and macrophage densities were measured. ResultsOn day 1, IOP was significantly reduced by 30% (p < 0.0001; n=25) while outflow facility (p = 0.306; n=15) and aqueous production (p = 0.163; n=9) were unchanged. As well, Schlemms canal filtration area was unchanged, however distal vessels were dilated (p < 0.001) at day 1 post ICP. Correspondingly, macrophage density was significantly increased around episcleral vessels (p < 0.0005) at day 1. Macrophage densities in Schlemms canal and trabecular meshwork, while unchanged at day 1, were significantly increased by day 3 (p < 0.0001). ConclusionsCoincident with significantly reduced IOP one day after ICP, there was an influx of macrophages into the distal portion of the conventional outflow tissues and a dilation of episcleral vessels, likely reducing distal outflow resistance. Our study demonstrates the importance of considering the drug delivery method to the eye due to its effects on the immune response and conventional outflow homeostasis.

physiology↗

bioRxiv2025

Reduced systemic autophagy by simultaneous loss of ATG4B, ATG4C and ATG4D leads to accelerated aging in mice

Autophagy is an essential catabolic pathway that safeguards cellular and tissue homeostasis, yet the systemic consequences of its impairment in mammals remain poorly defined because complete autophagy ablation is embryonic or perinatal lethal. Here, we generate ATG4A-only mice, a model in which ATG4A is the sole remaining ATG4 protease due to combined ATG4B/C/D deletion. Through comprehensive biochemical and cellular analyses, we delineate the in vivo substrate specificity of ATG4A and demonstrate that it sustains only minimal ATG8 priming, uncovering a previously unrecognized functional asymmetry within the mammalian ATG4-ATG8 system. ATG4A-only mice exhibit a profound but incomplete whole-body autophagy deficiency that disrupts multiple organ systems and triggers a premature aging syndrome marked by increased DNA damage, systemic senescence, metabolic dysfunction, and dramatically shortened lifespan. Integrating these findings with comparisons to additional ATG4-deficient models, we show that organismal longevity scales with residual autophagic competence. Together, our work reveals how graded reductions in autophagy integrity influence tissue fitness and aging, establishing autophagic capacity as a key determinant of mammalian lifespan.

cell biology↗

bioRxiv2025

Resident Tissue Macrophages Govern Intraocular Pressure Homeostasis

Intraocular pressure is tightly regulated by the conventional outflow tissues, preventing ocular hypertension that leads to neurodegeneration of the optic nerve, or glaucoma. Although macrophages reside throughout the conventional outflow tract, their role in regulating intraocular pressure remains unknown. Using macrophage lineage tracing approaches, we uncovered a dual macrophage ontogeny with distinct spatial organizations across the mouse lifespan. Long-lived, resident tissue macrophages concentrated in the trabecular meshwork and Schlemms canal, whereas short-lived monocyte-derived macrophages, instead, were abundant around distal vessels. Specific depletion of resident tissue macrophages triggered elevated intraocular pressure and outflow resistance, linked to aberrant extracellular matrix turnover in the resistance-generating tissues of the trabecular meshwork. This dysregulated physiology and tissue remodeling were not observed when we depleted monocyte-derived macrophages. Results show ontogeny and tissue-specific macrophage function within the outflow tract, uncovering the integral homeostatic role of resident tissue macrophages in resistance-generating tissues whose dysfunction is responsible for glaucoma.

immunology↗