Depletion of MCP-1 increases development of herpetic stromal keratitis by innate immune modulation

Abstract

Chemokines are important chemoattractant inflammatory molecules, but their interdependent network in disease pathogenesis remains unclear. Studies in mouse models have shown that herpetic stromal keratitis (SK) is produced by the consequence of a tissue-destructive immunoinflammatory reaction involving herpes simplex virus type 1 (HSV) infection. Here we found that ocular HSV infection leads to increased expression of monocyte chemoattractant protein-1 (MCP-1), one of the major chemoattractants for immune cells that express CCR2, in the SK cornea. However, MCP-1 is unlikely to be a chemoattractant for infiltrating Gr-1(+), CD11b(+) cells in SK, as these cells are found to be CCR2 negative. Nevertheless, infection of MCP-1(-/-) mice resulted in more severe SK lesion severity compared with WT mice (P<0.01). We demonstrated that the loss of MCP-1 in the SK cornea caused a significant overexpression of macrophage inflammatory protein-2 (MIP-2) (P<0.01) on days 2 and 4 postinfection and increased infiltration of inflammatory cells (Gr-1-high and CD11b(+)) expressing CXCR2, a receptor for MIP-2, into the cornea. Subsequently, increased infiltration of inflammatory cells accelerated by MIP-2 overexpression might result in the high production of inflammatory molecules, including vascular endothelial growth factor (VEGF) and IL-1beta in SK, as well as CpG oligodeoxynucleotide (ODN)-implanted eyes of MCP-1(-/-) mice. These results indicate that MCP-1 in the SK cornea might regulate the expression of other chemokines, as well as the infiltration of inflammatory cells and control development of SK.

Amniotic Membrane Transplantation Induces Apoptosis in T Lymphocytes in Murine Corneas with Experimental Herpetic Stromal Keratitis

“…41 It has been shown that CCL-2/MCP-1 depletion resulted in innate immune modulation and increased corneal inflammation as a result of MIP-2 overexpression. 42 In fact, we found increased amounts of MIP-2/CXCL2 in murine corneas with HSK and AMT. 24 Neutralizing antibodies to MIP-2 suppressed HSV-1-specific DTH and sharply reduced neutrophil accumulation in the ear pinna.…”

IL-2/Anti–IL-2 Antibody Complex Treatment Inhibits the Development but Not the Progression of Herpetic Stromal Keratitis

“…NK cell influx in infected tissues is coordinated by chemokines such as CCL2 (18). CCL2 is also upregulated in HSV-1 infected corneas (19). Therefore, we determined the levels of CCL2 in the corneal lysates from both groups of mice on day 2 post-infection.…”

Neuroprotectin D1 Reduces the Severity of Herpes Simplex Virus–Induced Corneal Immunopathology

“…***P 0.001. angiogenesis was recorded as described previously. 19 In reference to the angiogenic scoring system, the method relied on quantifying the degree of neovessel formation based on three primary parameters: the circumferential extent of neovessels (as the angiogenic response is not uniformly circumferential in all cases), the centripetal growth of the longest vessels in each quadrant of the circle, and the longest neovessel in each quadrant was identified and graded between 0 (no neovessel) and 4 (neovessel in the corneal center) in increments of 0.4 mm (radius of the cornea is 1.5 mm). According to this system, a grade of 4 for a given quadrant of the circle represents a centripetal growth of 1.5 mm toward the corneal center.…”