Chapter 1 of 3

Corneal macrophages: anatomy & immune privilege

Original teaching synthesis based on the review by Yaghmour A, Arabpour Z, Al-Khudari H, Djalilian A. "When Macrophages Heal and When They Scar: Timing in Corneal Fibrosis", Life 2026;16:1090 (open access), illustrated by Pr Éric Gabison's team.

The cornea is avascular but not devoid of immune cells: macrophages reside there permanently, at low density, mainly at the periphery and limbus, without compromising transparency or avascularity ^{[Yaghmour 2026]}. Their role is to survey the tissue, orchestrate defence against injury, and then close the inflammatory window at the right time to allow transparent healing.

This immune privilege rests on an active balance, not a simple absence: low expression of MHC molecules, absence of blood and lymphatic vessels, an anti-inflammatory microenvironment (soluble immunosuppressive factors, TGF-β, α-MSH, ACAID) and relative immune tolerance to grafts. Disrupting this balance — through trauma, infection or repeated surgery — exposes the cornea to dysregulated inflammation and fibrosis ^{[Streilein 2003]}.

Diagram of corneal structure: epithelium, Bowman's membrane, stroma, Descemet's membrane, endothelium, with innervation and immune privilege — Figure 1. Corneal anatomy and the basis of immune privilege: avascularity, dense innervation (trigeminal nerve, V1), stromal transparency and immune privilege (original illustration, Pr É. Gabison's team). Click to enlarge ⤢

Resident vs recruited populations

Two macrophage populations coexist in the cornea, with non-redundant and temporally distinct roles ^{[Yaghmour 2026]}:

Resident macrophages: of embryonic origin, they self-renew in place. They provide immune surveillance, maintain immune privilege, clear debris and drive early resolution of minor injuries. They are especially important for preserving stromal quiescence.
Monocyte-derived macrophages: rapidly recruited from the circulation via limbal vessels in response to epithelial injury, chemokine gradients and vascular leakage. They dominate during acute, severe injury and are the main source of the cytokines, growth factors and matrix-modifying enzymes that drive early defence and stromal remodelling.

The review's central message

Corneal fibrosis is not simply a consequence of macrophage presence: it reflects a failure to transition from recruited inflammatory programmes toward resident-like or resolution-phase states. The therapeutic target is therefore not to eliminate macrophages, but to restore their proper timing ^{[Yaghmour 2026]}.

Timeline of macrophage responses

The macrophage response to corneal injury follows a dynamic four-phase continuum, which determines the outcome of healing — transparent regeneration or fibrosis ^{[Yaghmour 2026]}.

Four phases, one clock

Timeline of macrophage responses in corneal healing and fibrosis
Phase	Time	Goal	Possible outcome
Early inflammatory	0 h – 1 to 3 days	Host defence and debris clearance	Infection control, initiation of repair
Early repair	3 to 7 days	Promotion of tissue repair	Effective repair
Resolution	> 7 days	Resolution of inflammation and restoration	Restoration of functional transparency
Chronic dysregulated	Weeks to months	Persistent inflammation and matrix deposition	Fibrosis, opacification, loss of transparency

Each phase is dominated by a distinct macrophage phenotype: the pro-inflammatory (M1-like) macrophage phagocytoses pathogens and debris and secretes IL-1β, TNF-α, IL-6, ROS and NO; intermediate states secrete growth factors (VEGF, PDGF) and initiate matrix remodelling; the pro-resolving (M2-like) macrophage clears apoptotic cells by efferocytosis and secretes IL-10 and low-dose TGF-β; if this transition fails, a persistent pro-fibrotic macrophage maintains sustained secretion of TGF-β, CTGF and PDGF, chronically activating myofibroblasts.

Timeline of macrophage responses in corneal healing and fibrosis: four phases, from pro-inflammatory macrophage to persistent pro-fibrotic macrophage — Figure 2. The functional polarization of corneal macrophages forms a **continuous spectrum**, from the pro-inflammatory pole (M1-like) to the pro-resolving/pro-fibrotic pole (M2 spectrum); the final phenotype depends on the tissue environment and the signals received (original illustration, Pr É. Gabison's team, after Yaghmour *et al.* 2026). Click to enlarge ⤢

Key message

The early pro-inflammatory phase is essential for host defence and the initiation of repair. An efficient transition toward pro-resolving macrophages determines the restoration of corneal transparency. Failure of this transition favours chronic inflammation and fibrosis.

When the macrophage turns rogue

Macrophages become pathogenic drivers of fibrosis when their inflammatory activation persists beyond the appropriate temporal window. In severe chemical injury, chronic infection, autoimmune disease or repeated surgical trauma, they maintain a pro-inflammatory and pro-fibrotic secretory profile well beyond the expected proliferative phase ^{[Yaghmour 2026]}. The cytokines and growth factors they then release reinforce fibroblast-to-myofibroblast differentiation, sustain excess extracellular matrix production and prevent resolution. They also indirectly promote angiogenesis and lymphangiogenesis — two breaches of immune privilege that perpetuate inflammatory cell influx and shift healing from a regenerative to a pathological mode.

Clinical pitfall

An eye that remains red and inflamed beyond the first week after corneal injury should not be read as simple slow healing: it is the warning sign of persistent pro-fibrotic macrophage activity, to be corrected before it locks in permanent opacity.

Glossary of abbreviations used in this course

Scientific abbreviations and acronyms used throughout the 10 pages of this course, listed alphabetically.

95% CI: 95% confidence interval
AAV: adeno-associated virus (gene-therapy viral vector)
ABCG2: ABCG2 transporter, a limbal stem-cell marker
AMT: amniotic membrane transplantation
anti-VEGF: anti-angiogenic treatment targeting VEGF
ASC: inflammasome adaptor protein (Apoptosis-associated Speck-like protein containing a CARD)
BrdU: bromodeoxyuridine, a cell-proliferation marker
CCL2: CCL2 chemokine, synonym of MCP-1; recruits circulating monocytes
CCR2: receptor for CCL2; marker of newly recruited monocytes/macrophages
CD147: cluster of differentiation 147; synonym of EMMPRIN and basigin
CD163: M2 macrophage marker; scavenger receptor for haemoglobin-haptoglobin
CD206: mannose receptor; marker of M2 polarization
CD74: cell-surface receptor for MIF
CDVA: corrected distance visual acuity
CGRP: calcitonin gene-related peptide
CTGF: connective tissue growth factor
CX3CL1: fractalkine, a chemokine involved in monocyte/macrophage recruitment
CXCR2/CXCR4: chemokine receptors, also receptors for MIF
DAMP: damage-associated molecular pattern
DESI: direct epithelial–stromal interaction
EGF: epidermal growth factor
EGFR: epidermal growth factor receptor
EMMPRIN: extracellular matrix metalloproteinase inducer; synonym of CD147
ETDRS: reference visual-acuity scale used in clinical research (Early Treatment Diabetic Retinopathy Study)
FasL: Fas ligand, an apoptosis-inducing protein
FISH: fluorescence in situ hybridisation
GAG: glycosaminoglycan(s)
GM-CSF: granulocyte-macrophage colony-stimulating factor
GVHD: graft-versus-host disease
HGF: hepatocyte growth factor
HIF-3α: hypoxia-inducible factor, 3-alpha subunit
HMGB1: high mobility group box 1, an alarmin released by injured cells (DAMP)
IFN-γ: interferon gamma
IGF-1: insulin-like growth factor 1
IL-1: interleukin-1
iNOS: inducible nitric oxide synthase
IPAS: inhibitory PAS domain protein
KGF: keratinocyte growth factor
LASIK: laser-assisted in situ keratomileusis
LogMAR: logarithmic visual-acuity scale
LOX: lysyl oxidase, a collagen cross-linking enzyme
LPS: bacterial lipopolysaccharide
M1: classically activated macrophage, pro-inflammatory profile
M2: alternatively activated macrophage, pro-resolving/reparative profile (subtypes M2a-M2d, M2eff)
MEN2B: multiple endocrine neoplasia type 2B
MerTK: receptor tyrosine kinase involved in efferocytosis
MIF: macrophage migration inhibitory factor
MRI: magnetic resonance imaging
NGF: nerve growth factor
NK: neurotrophic keratitis
NLRP3: NLRP3 inflammasome (NOD-, LRP- and pyrin domain-containing protein 3)
NO: nitric oxide
NSAID: nonsteroidal anti-inflammatory drug
PACAP: pituitary adenylate cyclase-activating polypeptide
PAF: platelet-activating factor
PAMP: pathogen-associated molecular pattern
PDGF: platelet-derived growth factor
PED: persistent epithelial defect
PEDF: pigment epithelium-derived factor
PGE₂: prostaglandin E2
PRK: photorefractive keratectomy (laser surface ablation)
pro-NGF: precursor form of NGF
RGTA: matrix-therapy ReGeneraTing Agent, e.g. Cacicol
rhNGF: recombinant human NGF (cenegermin)
ROS: reactive oxygen species
Smad: signalling proteins of the TGF-β pathway
SPK: superficial punctate keratitis
sVEGFR-1: soluble form of VEGF receptor-1 (= sFlt-1)
sVEGFR-3: soluble form of VEGF receptor-3
TGF-β: transforming growth factor beta
TIMP: tissue inhibitor of metalloproteinases
TLR: Toll-like receptor
TNF-α: tumour necrosis factor alpha
TRPV4: transient receptor potential vanilloid 4, a mechanosensitive ion channel
uPA: urokinase-type plasminogen activator
V1: ophthalmic branch of the trigeminal nerve
VEGF: vascular endothelial growth factor
VEGF-C: lymphangiogenic isoform of VEGF
VIP: vasoactive intestinal peptide
YAP/TAZ: Hippo pathway effectors, mechanosensors of matrix stiffness
α-SMA: alpha-smooth muscle actin, a myofibroblast marker