The naïve cornea is an avascular tissue but is well-reported to harbor antigen-presenting cells (APCs) [1]. These APCs are stratified in the different layers of the naïve cornea. Among APCs, CD11c + dendritic cells are reported in the basal layer of the corneal epithelium [2], whereas the CD45+CD11b + resident macrophages are shown in the corneal stroma of uninfected mouse cornea [3]. Similar stratification of APCs is noted in the human corneas. CD207+ Langerhans cells (LCs), a subpopulation of dendritic cells, are shown in the basal layer of the corneal epithelium, and CD68+ macrophages are reported in the anterior stroma of normal donor human corneas [4]. Although the functional significance of corneal APCs is not entirely understood, they are shown to mobilize to the site of infection upon corneal herpes simplex virus-1 (HSV-1) infection [4]. The factors that regulate the homing of these APCs in naïve cornea and their migration upon corneal HSV-1 infection are not fully understood.

Chemokine receptors are G-protein coupled receptors interacting with structurally similar protein molecules named chemokines [5]. The interaction between chemokines and chemokine receptors activates intracellular signaling pathways that play an essential role in homing, migration, proliferation, and survival of chemokine receptor-expressing cells [[6], [7], [8]]. CXCR4 is widely expressed among chemokine receptors and regulates physiological and pathological conditions [9,10]. CXCR4 protein is evolutionary conserved, and the human and mouse CXCR4 share 89% similarity [11,12]. The canonical chemokine ligand of CXCR4 is CXCL12, also known as stromal cell-derived factor-1 alpha (SDF-1α) [13]. CXCR4-SDF-1α signaling is known to play an important role in the homing of immune cells into bone marrow [14,15]. A recent study has shown CXCR4-mediated recruitment of CD11c + conventional dendritic cells in suture-induced corneal inflammation [16]. Similarly, the CXCR4-SDF-1α axis is reported to regulate hem-and lymphangiogenesis in sutured corneas in mice [17]. Even though the role of CXCR4 signaling is shown in sterile corneal inflammation, little is known about the characterization of CXCR4-expressing cells in uninfected and HSV-1-infected corneas.

In the current study, we detected CXCR4-expressing cells in the separated epithelium and stroma from uninfected murine corneas by flow cytometry. In epithelium, most CXCR4-expressing cells bear the signature of LCs, whereas most stromal CXCR4+ cells exhibit macrophage phenotype. Corneal HSV-1 infection resulted in a transient increase in CXCR4-expressing LCs in the epithelium. In addition to resident APCs, CXCR4 expression was noticed on infiltrated neutrophils and newly formed blood vessels in HSV-1 infected corneas. Our results suggest that manipulating CXCR4 signaling in HSV-1 infected corneas can have therapeutic implications in reducing the severity of herpes stromal keratitis (HSK).