Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H‐ferritin interact through the T‐cell immunoglobulin and mucin domain (Tim‐2) receptor in mice. H‐ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim‐2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H‐ferritin for meeting iron requirements and that these functions are mediated via the Tim‐1 receptor. Moreover, we also demonstrate the ability of H‐ferritin to block Sema4A‐mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV‐seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system. Main Points Semaphorin 4A uses Tim‐1 to induce apoptosis in mature oligodendrocytes. H‐ferritin delivers iron to mature oligodendrocytes via Tim‐1. Semaphorin 4A is elevated in the CSF of patients with white matter damage.