Murine endotoxin-induced uveitis, but not immune complex-induced uveitis, is dependent on the IL-8 receptor homolog.
OBJECTIVE
To determine the roles of the murine interleukin-8 receptor homolog (mIL-8Rh, neutrophil chemokine CXC receptor 2) and macrophage inflammatory protein-1alpha (MIP-1alpha, a CC chemokine) in two eye inflammation models: endotoxin-induced uveitis (EIU) and immune complex-induced uveitis (reverse passive Arthus reaction (RPAR) uveitis).


METHODS
For the EIU model, 250 ng E.coli endotoxin was injected into the vitreous of mIL-8Rh-/- mice or heterozygous littermate mIL-8Rh+/- controls and into MIP-1alpha-/- mice or congenic MIP-1alpha+/+ controls. Eyes were harvested after 24 h for histologic characterization of infiltrating cells and IL-6 bioassays. For the RPAR model, mouse antiserum against human serum albumin (HSA) was injected into the vitreous of mIL-8Rh-/-, mIL-8Rh+/-, MIP-1alpha-/-, and MIP-1alpha+/+ mice. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were harvested after 4 h for analysis.


RESULTS
RPAR resulted in the deposition of immune complexes at the ciliary area and iris with the subsequent development of uveitis. Genetic deficiency of mIL-8Rh reduced the median number of infiltrating cells in EIU by 63% (p < 0.01) but had no effect on RPAR-induced inflammation. In the EIU model, macrophages comprised a much higher percentage (45%) of infiltrating cells in mice lacking mIL-8Rh than in controls (17%). Loss of the MIP-1alpha gene had no apparent effect on RPAR uveitis and a 39% reduction of infiltrating cells in EIU that was not statistically significant. IL-6 activity in aqueous humor was much less in mice with RPAR uveitis than in those with EIU. Neither gene deletion had a significant impact on IL-6 levels in either disease model.


CONCLUSIONS
Chemokines acting via mIL-8Rh have a significant role in the induction of neutrophil infiltration during EIU but not during RPAR uveitis. MIP-1alpha is not critical for either EIU or RPAR-induced uveitis. The differential dependence on IL-8-like chemokines is in accord with the two forms ofuveitis having different etiologies and, therefore, potentially different optimal therapies.
Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Portland, USA.
B E
BE
Brito
L M
LM
O'Rourke
Y
Y
Pan
X
X
Huang
J M
JM
Park
D
D
Zamora
D N
DN
Cook
S R
SR
Planck
J T
JT
Rosenbaum
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001183:Arthus Reaction / Q000150:complications; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000235:genetics; D004731:Endotoxins; D004926:Escherichia coli; D006824:Hybridization, Genetic; D015850:Interleukin-6 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology*; D023062:Receptors, Interleukin-8A; D014605:Uveitis / Q000139:chemically induced* / Q000209:etiology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A