CD74 as a Potential Regulator of Microglia Function in the Pathogenesis of Experimental Autoimmune Encephalomyelitis (EAE)

CD74 (invariant chain, Ii) is a non-polymorphic type II transmembrane protein predominantly found on the surface of antigen-presenting cells (APCs). On the cell surface, CD74 functions as a receptor for the cytokine macrophage migration inhibitory factor (MIF), triggering a signaling cascade upon MIF binding. This cascade leads to the release of the intracellular domain of CD74 (CD74-ICD), which acts as a transcriptional regulator in normal and malignant cells.

Experimental Autoimmune Encephalomyelitis (EAE), a widely used murine model of multiple sclerosis (MS), is characterized by immune-mediated demyelination and neuroinflammation within the central nervous system (CNS). Recent evidence suggests that CD74 plays a crucial role in the pathogenesis of EAE. In this study, we investigated the multifaceted involvement of CD74 in EAE, including its effects on immune cell activation and recruitment, cytokine production, and neuroinflammatory responses.

Using CD74 full deficient mice and conditional knock out (cKO) transgenic murine models, we demonstrate that CD74 contributes significantly to disease severity and CD74-deficient (CD74-/-) mice are protected against the development of EAE. Furthermore, targeted knockout of CD74 in specific antigen-presenting cell populations or exclusively within the CNS results in a marked reduction in disease severity. While the transgenic mouse strains investigated showed a reduction in disease severity and delayed onset, mice with CD74 deficiency on microglial cells of the CNS exhibit were completely protected from disease onset and progression.

Collectively, these findings establish CD74 as a critical player in microglia function and EAE pathogenesis and highlight its potential as a therapeutic target for the prevention and treatment of EAE and MS.