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CCR2- and CCR2+ corneal macrophages exhibit distinct characteristics and balance inflammatory responses after epithelial abrasion.

ABSTRACT: Macrophages are distributed throughout the body and are crucial for the restoration of damaged tissues. However, their characteristics in the cornea and roles in the repair of corneal injures are unclear. Here we show that corneal macrophages can be classified as CCR2- macrophages, which already exist in the cornea at embryonic day 12.5 (E12.5) and are similar to yolk sac-derived macrophages, microglia, in phenotype and gene expression, and CCR2+ macrophages, which do not appear in the cornea until E17.5. At a steady state, CCR2- corneal macrophages have local proliferation capacity and are rarely affected by monocytes; however, following corneal epithelial abrasion, most CCR2- corneal macrophages are replaced by monocytes. In contrast, CCR2+ macrophages are repopulated by monocytes under both a steady-state condition and following corneal wounding. Depletion of CCR2+ macrophages decreases corneal inflammation after epithelial abrasion, whereas depletion of CCR2- macrophages increases inflammation of the injured cornea. Loss of either cell type results in a delay in corneal healing. These data indicate that there are two unique macrophage populations present in the cornea, both of which participate in corneal wound healing by balancing the inflammatory response.

SUBMITTER: Liu J

PROVIDER: S-EPMC5562841 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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CCR2- and CCR2+ corneal macrophages exhibit distinct characteristics and balance inflammatory responses after epithelial abrasion.

Liu J J Xue Y Y Dong D D Xiao C C Lin C C Wang H H Song F F Fu T T Wang Z Z Chen J J Pan H H Li Y Y Cai D D Li Z Z

Mucosal immunology 20170125 5

Macrophages are distributed throughout the body and are crucial for the restoration of damaged tissues. However, their characteristics in the cornea and roles in the repair of corneal injures are unclear. Here we show that corneal macrophages can be classified as CCR2- macrophages, which already exist in the cornea at embryonic day 12.5 (E12.5) and are similar to yolk sac-derived macrophages, microglia, in phenotype and gene expression, and CCR2+ macrophages, which do not a ...[more]

PMID: 28120849

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Project description:Corneal abrasion not only damages the epithelium but also induces stromal keratocyte death at the site of injury. While a coordinated cascade of inflammatory cell recruitment facilitates epithelial restoration, it is unclear if this cascade is necessary for keratocyte recovery. Since platelet and neutrophil (PMN) recruitment after corneal abrasion is beneficial to epithelial wound healing, we wanted to determine if these cells play a role in regulating keratocyte repopulation after epithelial abrasion. A 2 mm diameter central epithelial region was removed from the corneas of C57BL/6 wildtype (WT), P-selectin deficient (P-sel-/-), and CD18 hypomorphic (CD18hypo) mice using the Algerbrush II. Corneas were studied at 6h intervals out to 48h post-injury to evaluate platelet and PMN cell numbers; additional corneas were studied at 1, 4, 14, and 28 days post injury to evaluate keratocyte numbers. In WT mice, epithelial abrasion induced a loss of anterior central keratocytes and keratocyte recovery was rapid and incomplete, reaching ~70% of uninjured baseline values by 4 days post-injury but no further improvement at 28 days post-injury. Consistent with a beneficial role for platelets and PMNs in wound healing, keratocyte recovery was significantly depressed at 4 days post-injury (~30% of uninjured baseline) in P-sel-/- mice, which are known to have impaired platelet and PMN recruitment after corneal abrasion. Passive transfer of platelets from WT, but not P-sel-/-, into P-sel-/- mice prior to injury restored anterior central keratocyte numbers at 4 days post-injury to P-sel-/- uninjured baseline levels. While PMN infiltration in injured CD18hypo mice was similar to injured WT mice, platelet recruitment was markedly decreased and anterior central keratocyte recovery was significantly reduced (~50% of baseline) at 4-28 days post-injury. Collectively, the data suggest platelets and platelet P-selectin are critical for efficient keratocyte recovery after corneal epithelial abrasion.

Project description:BackgroundCorneal immune cells interact with corneal sensory nerves during both homeostasis and inflammation. This study sought to evaluate temporal changes to corneal immune cell density in a mouse model of epithelial abrasion and nerve injury, and to investigate the immunomodulatory effects of topical decorin, which we have shown previously to promote corneal nerve regeneration.MethodsBilateral corneal epithelial abrasions (2 mm) were performed on C57BL/6J mice. Topical decorin or saline eye drops were applied three times daily for 12 h, 24 h, 3 days or 5 days. Optical coherence tomography imaging was performed to measure the abrasion area. The densities of corneal sensory nerves (β-tubulin III) and immune cells, including dendritic cells (DCs; CD11c+), macrophages (Iba-1+) and neutrophils (NIMP-R14+) were measured. Cx3cr1gfp/gfp mice that spontaneously lack resident corneal intraepithelial DCs were used to investigate the specific contribution of epithelial DCs. Neuropeptide and cytokine gene expression was evaluated using qRT-PCR at 12 h post-injury.ResultsIn decorin-treated corneas, higher intraepithelial DC densities and lower neutrophil densities were observed at 24 h after injury, compared to saline controls. At 12 h post-injury, topical decorin application was associated with greater re-epithelialisation. At 5 days post-injury, corneal stromal macrophage density in the decorin-treated and contralateral eyes was lower, and nerve density was higher, compared to eyes treated with saline only. Lower expression of transforming growth factor beta (TGF-β) and higher expression of CSPG4 mRNA was detected in corneas treated with topical decorin. There was no difference in corneal neutrophil density in Cx3cr1gfp/gfp mice treated with or without decorin at 12 h.ConclusionsTopical decorin regulates immune cell dynamics after corneal injury, by inhibiting neutrophils and recruiting intraepithelial DCs during the acute phase (< 24 h), and inhibiting macrophage density at the study endpoint (5 days). These immunomodulatory effects were associated with faster re-epithelialisation and likely contribute to promoting sensory nerve regeneration. The findings suggest a potential interaction between DCs and neutrophils with topical decorin treatment, as the decorin-induced neutrophil inhibition was absent in Cx3cr1gfp/gfp mice that lack corneal epithelial DCs. TGF-β and CSPG4 proteoglycan likely regulate decorin-mediated innate immune cell responses and nerve regeneration after injury.

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CCR2- and CCR2+ corneal macrophages exhibit distinct characteristics and balance inflammatory responses after epithelial abrasion.

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CCR2<sup>-</sup> and CCR2<sup>+</sup> corneal macrophages exhibit distinct characteristics and balance inflammatory responses after epithelial abrasion.

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