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Deletion of IL-4R in the BALB/c mouse is associated with altered lesion topography and susceptibility to experimental autoimmune encephalomyelitis.

Orian, JM;Keating, P;Downs, LL;Hale, MW;Jiang, X;Pham, H;LaFlamme, AC;

The regulation of cytokine expression by immune deviation from a pro-inflammatory to anti-inflammatory or regulatory milieu is crucial to the prevention of permanent central nervous system (CNS) damage in neuroinflammation. Earlier studies in the murine experimental autoimmune encephalomyelitis (EAE) model pointed to an anti-inflammatory role for the Th2 cytokine, IL-4, which was not confirmed in IL-4R-deficient mice (IL-4R(-/-)). To examine the pathological consequences of loss of responsiveness to Th2 cytokines, we compared lesion evolution in IL-4R(-/-) and wild type (WT) BALB/c mice immunized with PLP180-199 and investigated how altering the magnitude of the antigen-specific autoimmune response in this model affected the pathology. We found that while changing the magnitude of the peripheral antigen-specific response differentially affected the incidence of clinical disease in WT BALB/c relative to IL-4R(-/-) mice, the differences in incidence did not correlate to differences in pro-inflammatory cytokine production. Additionally, although only approximately 75% of WT mice developed clinical disease, lesions were observed in 100% of the mice, principally in the cerebellum, mid-brain and cerebral hemispheres, and lesion load increased with increasing pro-inflammatory cytokine production. Despite being resistant to disease induction with increasing pro-inflammatory cytokine production, lesion incidence in IL-4R-deficient animals was equal to their WT counterparts. However, lesion severity in IL-4R-deficient animals was preferentially reduced in the mid-brain and cerebral hemispheres. From these studies, we conclude that signaling through IL-4R has little effect on regulating the peripheral pro-inflammatory cytokine profile in this EAE variant but has distinct effects on the determination of lesion topography.