Enhanced MIF/CD74 axis activity shapes B cell functioning following traumatic spinal cord injury

Abstract

A traumatic spinal cord injury (SCI) severely damages the nerve tissue of the spinal cord, often leading to long-term impairment of motor, sensory and autonomic functions. During a secondary injury phase, an inflammatory immune response is initiated. Current evidence points toward involvement of B cells and the macrophage migration inhibitory factor (MIF)/CD74 axis in SCI pathology. This study aimed to map the complete MIF/CD74 axis across the immune system and analyze its impact on B cell function after traumatic SCI. Peripheral blood samples were obtained from a total cohort of 90 healthy controls (HC) and 70 SCI patients. SCI samples were collected longitudinally in the acute (0 weeks post-SCI), subacute (2 weeks post-SCI), intermediate (3-18 weeks post-SCI) and chronic (26-52 weeks post-SCI) phases post-injury. MIF levels in plasma of SCI patients and HC were measured using ELISA. Relative and absolute levels of immune and B cell subsets, as well as expression of members of the MIF/CD74 axis, were studied using high-dimensional flow cytometry. The functional relevance of MIF/CD74 axis signaling on B cell functions was investigated using in vitro blocking assays. SCI triggered an early immune cell reduction, characterized by decreased absolute numbers of total and MIF/CD74 axis-expressing B cells and immune cells. In contrast, the MIF/CD74 axis was upregulated as MIF receptor surface expression on B cell subsets, as well as frequencies of CD74(+), CD44(+) and CXCR4(+) B cells, were increased during the subacute/intermediate phase post-SCI. MIF plasma levels were increased in SCI patients, yet MIF expression levels were reduced within circulating immune cells, suggesting that the injured spinal cord is the main source of MIF. Importantly, decreased B cell proliferation, activation and cytokine production were observed after blocking of CD74, CD44 or MIF in primary B cells of SCI patients and HC. The observed effects were more pronounced in SCI B cells, highlighting their stronger dependence on MIF/CD74 axis signaling. In conclusion, the complete MIF/CD74 axis plays an important role in post-SCI B cell responses. Our findings warrant further investigation of the MIF/CD74 axis as a potential target for immunomodulatory strategies in SCI treatment.