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

Abstract

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-4Rα-deficient mice (IL-4Rα^−/−). To examine the pathological consequences of loss of responsiveness to Th2 cytokines, we compared lesion evolution in IL-4Rα^−/− and wild type (WT) BALB/c mice immunized with PLP_180–199 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-4Rα^−/− 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-4Rα-deficient animals was equal to their WT counterparts. However, lesion severity in IL-4Rα-deficient animals was preferentially reduced in the mid-brain and cerebral hemispheres. From these studies, we conclude that signaling through IL-4Rα 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.

• Atypical EAE
• cerebellar lesions
• cortical lesions
• EAE-resistant variant
• multiple sclerosis
• neuropathology

Acknowledgements

We thank Antonio Jimenez, Phuc Dang and Claretta D’Souza for assistance with the preparation of illustrations and Sara Mirmoeini for her technical assistance.

Declaration of interest

Dr J.M. Orian reports having received travel funds and grant support from Novartis Pharmaceuticals Australia. The remaining authors report no disclosures. The authors are solely responsible for the generation of data and writing of this manuscript.

This work was supported by awards from the National Multiple Sclerosis Society and from the Neurological Foundation of New Zealand (0828-PG) and equipment grants from the Ramaciotti and RL Cooper Foundations. LLD was the recipient of a scholarship from Multiple Sclerosis Research Australia.