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.
Brito
B E
BE
Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Portland, USA.
O'Rourke
L M
LM
Pan
Y
Y
Huang
X
X
Park
J M
JM
Zamora
D
D
Cook
D N
DN
Planck
S R
SR
Rosenbaum
J T
JT
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