Pro-resolving lipid mediator lipoxin A4 attenuates neuro-inflammation by modulating T cell responses and modifies the spinal cord lipidome

Abstract

The chronic neuro-inflammatory character of multiple sclerosis (MS) suggests that the natural process to resolve inflammation is impaired. This protective process is orchestrated by specialized pro-resolving lipid mediators (SPMs), but to date, the role of SPMs in MS remains largely unknown. Here, we provide in vivo evidence that treatment with the SPM lipoxin A₄ (LXA₄) ameliorates clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and inhibits CD4⁺ and CD8⁺ T cell infiltration into the central nervous system (CNS). Moreover, we show that LXA₄ potently reduces encephalitogenic Th1 and Th17 effector functions, both in vivo and in isolated human T cells from healthy donors and patients with relapsing-remitting MS. Finally, we demonstrate that LXA₄ affects the spinal cord lipidome by significantly reducing the levels of pro-inflammatory lipid mediators during EAE. Collectively, our findings provide mechanistic insight into LXA₄-mediated amelioration of neuro-inflammation and highlight the potential clinical application of LXA₄ for MS.

Keywords: EAE; SPMs; T cells; central nervous system; experimental autoimmune encephalomyelitis; lipidomics; lipoxin A(4); multiple sclerosis; neuro-inflammation; resolution of inflammation; specialized pro-resolving lipid mediators; spinal cord.