Macrophage/microglial recruitment and chemokine function in CNS demyelination.

摘要

Peripheral macrophage infiltration and the expression of chemokines (small chemotactic proteins known to regulate leukocyte recruitment and function) characterize many CNS demyelinating diseases. I hypothesized that chemokines and their receptors play roles in regulating peripheral macrophage recruitment in two murine models of CNS demyelination: (1) the cuprizone intoxication model and (2) the twitcher mouse, a murine model of globoid cell leukodystrophy. Although both models of demyelination show expression of similar chemokines and receptors, the studies here, using gene knockout mice, define functional differences on disease outcome.; Peripheral macrophage are known to be recruited into the CNS of twitcher mice during demyelination, but it was unclear if they similarly contribute to the robust Mac-1+ cellular accumulation within the CNS of mice fed with cuprizone. In Chapter 2, I use both flow cytometry and GFP + bone marrow-chimeric mice to demonstrate that peripheral macrophage do infiltrate into the brain during cuprizone-induced demyelination, despite a substantial microglial response and an intact blood brain barrier.; In Chapter 3, I examine the expression of chemokines and their receptors and test the in vivo function of MIP-1α and one of its receptors, CCR5, in cuprizone-induced demyelination. The importance of MIP-1α was demonstrated by MIP-1α−/− mice, which show delayed demyelination that correlates with decreased microglial/macrophage accumulation and TNFα protein levels when compared to wild type mice. In contrast, CCR5−/− mice do not display any differences from wild type mice during cuprizone exposure, suggesting that other receptors for MIP-1α must be involved.; The role of MIP-1α and CCR5 was similarly examined in twitcher mice in Chapter 4. In contrast to the cuprizone intoxication study, however, the absence of MIP-1α does not alter the course of disease in twitcher mice. However, CCR5−/− twitcher mice display enhanced clinical twitching and decreased lifespan compared to CCR5+/+ twitcher mice, suggesting that other chemokines besides MIP-1α are binding CCR5. The potential mechanisms for this protective role for CCR5 and the reduced severity of disease are discussed.; This work demonstrates that peripheral cells are recruited into the CNS during demyelination, even in the presence of an intact blood-brain barrier, and highlights both the harmful and beneficial effects chemokines and their receptors have in CNS demyelinating diseases.