Shi 2025 — Choroidal mast cells drive choroidal thinning via MC degranulation

One-paragraph summary

Mechanistic primary study in lens-induced myopia (LIM) mouse model using genetic, pharmacological, and rescue manipulations to establish choroidal mast cell degranulation as the necessary mechanism for choroidal thinning that accompanies axial elongation in myopia. Three experimental arms supplied causal evidence: (a) LIM was successfully induced in wild-type C57BL/6 mice but significantly suppressed in MC-deficient mice (Mcpt5/Cma1DTR/+); (b) suprachoroidal injection of peritoneal MCs into MC-deficient mice rescued myopia progression, restoring both axial elongation and choroidal thinning; (c) topical cromolyn sodium and pemirolast potassium — both MC stabilizers that inhibit degranulation — blocked both MC degranulation and myopia progression. For the FM project, this paper extends the H2 mast-cell axis directly to retinal/choroidal tissue using the same MC stabilizers (cromolyn) already in the project ontology. It demonstrates that choroidal MCs are a functional effector population (not merely anatomically present), with degranulation producing measurable tissue-level structural change (choroidal thinning) that can be non-invasively imaged by OCT. This makes choroidal thickness a candidate biomarker for H2-MC chain activity in retinal tissue.

Claims as triples

• choroidal_mast_cell — present_in → choroid [evidence: choroidal flatmount staining; confidence: established]
• choroidal_mast_cell — causes → choroidal_thinning [evidence: MC-deficient mice show suppressed LIM; PMC injection rescues; confidence: established (in mouse model)]
• cromolyn — modulates → choroidal_mast_cell [evidence: topical cromolyn blocks degranulation + myopia progression; confidence: established (in mouse model)]
• pemirolast — modulates → choroidal_mast_cell [evidence: same paradigm as cromolyn; confidence: established (in mouse model)]
• mast_cell — present_in → choroid [extends existing project mast_cell entity to choroidal anatomical site; confidence: emerging in FM context]
• choroidal_thickness — predicts → mast_cell_activity [inferred — degranulation drives thinning, OCT thickness is a candidate non-invasive readout; confidence: inferred for FM, established mechanistically in mouse]

Methods note

C57BL/6 wild-type mice and Mcpt5/Cma1DTR/+ mast-cell-deficient mice (a Cre-loxP conditional MC ablation system). Lens-induced myopia (LIM) induced by monocular -30 D lens wearing. Three intervention arms: (a) MC-deficient mice vs. WT comparison; (b) suprachoroidal injection of peritoneal MCs (PMCs) into MC-deficient mice for rescue; (c) topical cromolyn sodium and pemirolast potassium in LIM mice. Outcome measures: ocular refraction (autorefractor), axial length (ocular biometry), choroidal thickness (OCT), and choroidal MC degranulation evaluated by choroidal flatmount staining.

Limitations

• Mouse model of myopia, not FM. Direct translational relevance to FM requires demonstrating choroidal MC involvement in FM patients specifically.
• Lens-induced myopia is a mechanical / refractive stimulus, not an autoimmune or inflammatory trigger. Whether the same choroidal-MC mechanism operates under FM-relevant triggers (FM-IgG-MRGPRX2, substance P, estrogen) is not directly tested.
• Cromolyn and pemirolast are non-selective MC stabilizers; the paper does not dissect MRGPRX2-specific vs. other-receptor-mediated activation.
• MC ablation in Mcpt5/Cma1DTR/+ may affect MC populations beyond the choroid; rescue experiment (suprachoroidal PMC injection) addresses but does not fully resolve this.

Open questions raised

• Does choroidal MC degranulation occur in FM patients, and if so, does it correlate with anti-SGC IgG titer, HαT status, and serum tryptase? (extension of Q24 / Q44 / Q80 to retinal tissue)
• Does choroidal thickness on OCT serve as a non-invasive biomarker of choroidal MC activity in FM patients? (Q-Re-3 in the open-questions retinal section)
• Does topical or systemic cromolyn / barzolvolimab modify choroidal thickness in FM patients? (Q-Re-7)
• Is the choroidal MC population the same MC population implicated by Amato 2026 (gluteofemoral adipose) and Wang 2025 (endometriosis)? — i.e., are these tissue-specific MC pools or a single circulating-precursor-derived population?

Triangulation notes

• Extends the H1×H2 unified mechanism to retinal tissue. Sanchez 2025 establishes MRGPRX2 on mast cells as the receptor for FM-IgG-driven activation. MRGPRX2 is expressed on choroidal MCs per existing receptor pharmacology literature. The Shi 2025 paradigm + Sanchez 2025 mechanism predict that FM-IgG should drive choroidal MC degranulation → choroidal thinning → OCT-measurable readout.
• Supplies the mechanistic anchor for the §4 retinal mapping in retinal-biomarker-diagnostic-priority.md. Specifically the H2 row of that table (choroidal MC, OCT choroidal thickness, MC mediator panel).
• Aligns with I-1 calcium intersection (calcium-dysregulation-hypothesis.md v0.2): MC degranulation operates through STIM1/Orai1 SOCE downstream of MRGPRX2/NK1R/ER-IP3R Ca²⁺ release. The choroidal MC population should respond to CRAC channel blockers (Auxora-class) and MRGPRX2 antagonists (barzolvolimab) per the same mechanism as the gluteofemoral adipose MC population.
• Closes a previously-implicit assumption in the project's H2 chain: that MC populations relevant to FM are tissue-distributed beyond just gluteofemoral adipose. Choroidal MCs are anatomically distant from gfWAT but functionally homologous, supporting a multi-tissue H2-chain framework.

Bridges

• B-Re-2 (Choroidal mast cells ↔ FM-MC mechanism extension). One endpoint at choroidal tissue (this paper, in myopia model), other endpoint at FM-MC chain (Sanchez 2025, Aitella 2026, Amato 2026). Confidence: bridging until direct FM patient data demonstrates choroidal MC degranulation. Closing this bridge: choroidal-thickness-on-OCT measurement in anti-SGC IgG-positive FM patients with cromolyn or barzolvolimab cross-over.

Cure-path implications

The choroidal MC mechanism offers a potential non-invasive trial endpoint for any H2-targeting cure-path arm: cromolyn, barzolvolimab, CDX-0159, NK1R antagonist trials in FM could use choroidal thickness on OCT as a measure of target engagement. This is a substantive value-add to the cure-path program design because the existing pharmacodynamic markers for MC-targeting agents (serum tryptase, urinary methylhistamine) are noisy, subject to biological variability, and not well-correlated with clinical response. Choroidal thickness change post-treatment in the same patient is a quantitative, repeated-measurement-tolerant readout.