Protection from EAE by IL-4Ralpha(-/-) macrophages depends upon T regulatory cell involvement.
The administration of Th2 cytokines or immune deviation to a Th2 phenotypic response has been shown to protect against the autoimmune pathology of experimental autoimmune encephalomyelitis (EAE). To better understand the function of Th2 cytokines in the induction stage of EAE in the absence of an overt Th2 response, we immunized IL-4 receptor alpha-deficient (IL-4Ralpha(-/-)) mice, which are unable to respond to either IL-4 or IL-13. Contrary to expectations, mice lacking IL-4Ralpha had a lower incidence of EAE and a delayed onset compared to WT BALB/c mice; however, this delay did not correlate to an alteration in the Th1/Th17 cytokine balance. Instead, IL-4Ralpha-responsive macrophages were essential promoters of disease as macrophage-specific IL-4Ralpha-deficient (LysM(cre)IL-4Ralpha(-/lox)) mice were protected from EAE. The protection afforded by IL-4Ralpha-deficiency was not due to IL-10-, IFN-gamma-, NO- or IDO-mediated suppression of T-cell responses but was dependent upon the presence of regulatory T cells (Tregs). This investigation highlights the importance of macrophages and Tregs in regulating central nervous system inflammation and demonstrates that macrophages activated in the absence of Th2 cytokines can promote disease suppression by Tregs.
Keating
Paula
P
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
O'Sullivan
David
D
Tierney
Joanna B
JB
Kenwright
Diane
D
Miromoeini
Sara
S
Mawasse
Lina
L
Brombacher
Frank
F
La Flamme
Anne C
AC
D019264:Adoptive Transfer / Q000379:methods; D017668:Age of Onset; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015994:Incidence; D008198:Lymph Nodes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D053662:Interleukin-4 Receptor alpha Subunit
D016207:Cytokines; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit