Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease

Abstract

The discovery that chemokines and their receptors are expressed by a variety of cell types within the normal adult central nervous system (CNS) has led to an expansion of their repertoire as molecular interfaces between the immune and nervous systems. Thus, CNS chemokines are now divided into those molecules that regulate inflammatory cell migration into the CNS and those that initiate CNS repair from inflammation-mediated tissue damage. Work in our laboratory throughout the past decade has sought to elucidate how chemokines coordinate leukocyte entry and interactions at CNS endothelial barriers, under both homeostatic and inflammatory conditions, and how they promote repair within the CNS parenchyma. These studies have identified several chemokines, including CXCL12 and CXCL10, as critical regulators of leukocyte migration from perivascular locations. CXCL12 additionally plays an essential role in promoting remyelination of injured white matter. In both scenarios we have shown that chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

Figure 1

Chemokines mediate repair in the adult CNS. Following demyelination, CXCL12 and its receptors, CXCR4 and CXCR7, are upregulated on astrocytes and endothelial cells. CXCL12 binding to CXCR4 on OPCs induces proliferation and maturation into myelin-producing oligodendrocytes. CXCR7 regulates CXCR4 activation by sequestering CXCL12 into lysosomal compartments for degradation.

Figure 2

Neuroprotective roles of chemokines in response to viral infection of the CNS. Functional roles of chemokines in attracting and activating lymphocytes into the CNS during acute viral infection. Monocytes are attracted into the CNS via the chemokine CCL5 and its receptor CCR5. Macrophages produce IL-1β within the CNS and ensure full activation and CXCL12-mediated interactions of infiltrating leukocytes. CXCR4-expressing lymphocytes are captured by endothelial expression of CXCL12 within the perivascular spaces, which promotes CD4⁺ T-cell help to infiltrate CD8⁺ T lymphocytes. In addition to full activation, lymphocyte egress from perivascular spaces requires CD40. During the acute stage of disease, virally infected neurons secrete CXCL10 and CCL5 that attract activated T lymphocytes bearing the receptor CXCR3 and/or CCR5 into the parenchyma. CD8⁺ and CD4⁺ T lymphocytes mediate viral control through direct cytolytic activity and/or cytokine secretion.