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.

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

“…Much evidence showing that macrophages can respond to CCL2 also comes from studies done on osteoclasts, which are tissue-resident macrophages (102)(103)(104)(105). Concluding, it seems that macrophages represent a wide spectrum of differently polarized cells wherein some subsets do express CCR2 and are able to respond to CCL2 while others do not (171)(172)(173). Regulation of cell expression of this chemokine receptor may represent a neat way of controlling site-specific macrophage responses to CCL2.…”

The mouse autonomic nervous system modulates inflammation and epithelial renewal after corneal abrasion through the activation of distinct local macrophages

“…[5][6][7][8][9][10] After corneal abrasion, injured epithelial cells and keratocytes rapidly produce proinflammatory cytokines, such as interleukin (IL)-1, keratinocyte chemoattractant, LIX (a murine neutrophil-chemoattractant chemokine), macrophage inflammatory protein 1α (MIP-1α), tumor necrosis factor (TNF)-α, IL-6, 11 IL-17, 6 IL-20, 12 IL-22, 10 IL-25, and IL-33. 9 These cytokines recruit immune cells into the wound area and influence reepithelialization by different mechanisms. 5 Neutrophils are the first immune cell type to respond and massively populate the site of the corneal abrasion, where they release proteolytic enzymes and growth factors that help clear matrix debris and support nerve regrowth in the cornea.…”

Neutrophils Facing Biofilms: The Battle of the Barriers

“…Now, potential answers to these longstanding questions are stemming from a new study that focused on another more accessible organ, the eye. Long thought to be an immune-privileged site, new studies show that myeloid cells are recruited to the cornea upon abrasive damage (Liu et al, 2017). P. aeruginosa causes the majority of bacterial keratitis infections in immune compromised patients or healthy individuals using contact lenses.…”