Neutrophil-dominant experimental autoimmune uveitis in CC-chemokine receptor 2 knockout mice.
OBJECTIVE
Murine experimental autoimmune uveitis (EAU) is an animal model of human uveitis. It has been demonstrated that ocular-infiltrating macrophages are crucial for EAU induction, and monocyte chemoattractant protein-1 (MCP-1) was actually upregulated in the eye. CC chemokine receptor-2 (CCR2) is the receptor of MCP-1, and macrophages fail to recruit particular lesions in CCR2 knockout (KO) mice. To confirm the role of macrophages in EAU, we examined EAU in CCR2 KO mice.


METHODS
CCR2 KO mice and wild-type (WT) mice that had the same genetic background were immunized with human interphotoreceptor retinoid-binding protein peptide 1-20 emulsified in complete Freund's adjuvant. At multiple time-points, EAU severity was evaluated based on microscopic fundus observation and histological examination. To examine the phenotype of retinal-infiltrating cells, single cells were prepared from the eye and analysed by flow cytometry.


RESULTS
In WT mice, EAU was induced at the peak of day 16 and marked macrophage infiltration was observed. Although macrophages failed to be recruited into the eye in CCR2 KO mice, severe uveitis was induced unexpectedly. Flow cytometry and histology revealed that most of the infiltrating cells were neutrophils. We also compared the intraocular chemokine concentrations between WT mice and KO mice. Two CXC chemokine (monokine induced by interferon-γ and interferon-γ-inducible protein-10) were upregulated in KO mice.


CONCLUSIONS
Interphotoreceptor retinoid-binding protein peptide immunization caused neutrophil-dominant uveitis in CCR2 KO mice. In the absence of macrophages, neutrophils can be alternatively recruited and can cause tissue damage.
Sonoda
Koh-Hei
KH
Department of Ophthalmology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan. sonodak@med.kyushu-u.ac.jp
Yoshimura
Takeru
T
Egashira
Kensuke
K
Charo
Israel F
IF
Ishibashi
Tatsuro
T
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D054390:Receptors, CCR2 / Q000502:physiology*; D012173:Retinitis / Q000276:immunology; D012177:Retinol-Binding Proteins; D018417:Th1 Cells / Q000276:immunology; D015866:Uveitis, Posterior / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D018932:Chemokine CCL2; D016207:Cytokines; D005136:Eye Proteins; D054390:Receptors, CCR2; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C491768:Ccl2 protein, mouse