Altered chemokine profile associated with exacerbated autoimmune pathology under conditions of genetic interferon-gamma deficiency.
OBJECTIVE
A prior study showed that mice deficient in IFN-gamma (GKO) are more susceptible to experimental autoimmune uveitis (EAU) than are wild-type (WT) mice. Histopathology of uveitic eyes revealed that the ocular infiltrate in GKO mice was dominated by neutrophils and eosinophils rather than by mononuclear cells, as in WT mice. The present study was conducted to explore the differential expression of chemokine(s) likely to account for the distinct inflammatory cell composition in uveitic eyes of WT and GKO mice.


METHODS
Mice were immunized to induce EAU. Lymph nodes draining the site of the immunization and the eyes were collected at different time points for chemokine analysis. Microarray, real-time PCR and protein analyses were performed to examine the expression of chemokines in WT and GKO mice.


RESULTS
Many chemokines were differentially upregulated in GKO versus WT mice. Expression of the Th1-associated chemokines CXCL10, CXCL9, CCL5, and CXCL11 was elevated in WT mice, whereas the Th2-associated chemokines CCL11, CCL17, and CCL1 and the Th17-associated chemokines CCL22 and CXCL2 were elevated in the GKO mice. Depletion of granulocytes abrogated EAU in both WT and GKO mice.


CONCLUSIONS
These results suggest that Th1-associated chemokines play a critical role in the attraction of mononuclear cells to the eyes in the presence of IFN-gamma, while in the absence of this cytokine, Th2- and Th17-related chemokines may be the key elements for influx of granulocytes.
Su
Shao Bo
SB
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1857, USA.
Grajewski
Rafael S
RS
Luger
Dror
D
Agarwal
Rajeev K
RK
Silver
Phyllis B
PB
Tang
Jun
J
Tuo
Jingsheng
J
Chan
Chi-Chao
CC
Caspi
Rachel R
RR
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D004804:Eosinophils / Q000502:physiology; D005136:Eye Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006098:Granulocytes / Q000502:physiology; D007371:Interferon-gamma / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000302:isolation & purification; D012177:Retinol-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014605:Uveitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000099214:Retinol-Binding Proteins, Interstitial
D018925:Chemokines; D005136:Eye Proteins; D007371:Interferon-gamma; D012313:RNA; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial