Absence of CCL2 and CCL3 Ameliorates Central Nervous System Grey Matter But Not White Matter Demyelination in the Presence of an Intact Blood–Brain Barrier

Abstract

A broad spectrum of diseases is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation, among multiple sclerosis (MS). Our knowledge regarding the factors triggering gliosis and demyelination is scanty. Chemokines are pivotal for microglia and astrocyte activation and orchestrate critical steps during the formation of central nervous system (CNS) demyelinating lesions. Redundant functions of chemokines complicate, however, the study of their functional relevance. We used the cuprizone model to study redundant functions of two chemokines, CCL2/MCP1 and CCL3/MIP1α, which are critically involved in the pathological process of cuprizone-induced demyelination. First, we generated a mutant mouse strain lacking functional genes of both chemokines and demonstrated that double-mutant animals are viable, fertile, and do not present with gross abnormalities. Astrocytes and peritoneal macrophages, cultured form tissues of these animals did neither express CCL2 nor CCL3. Exposure to cuprizone resulted in increased CCL2 and CCL3 brain levels in wild-type but not mutant animals. Cuprizone-induced demyelination, oligodendrocyte loss, and astrogliosis were significantly ameliorated in the cortex but not corpus callosum of chemokine-deficient animals. In summary, we provide a novel powerful model to study the redundant function of two important chemokines. Our study reveals that chemokine function in the CNS redounds to region-specific pathophysiological events.

Sex differences in glia reactivity after cortical brain injury

“…Another possible explanation for the sex‐difference in the number of Iba1 immunoreactive cells at the lesion border could be a different rate of infiltration of peripheral immune cells, given that Iba1 is also expressed by macrophages and that the breakdown of the blood‐brain barrier facilitates a massive invasion of blood cells into the brain parenchyma. This phenomenon partially depends on the molecules expressed by the astrocytes forming the glial scar, such as the chemokines CCL2 and CCL3 (Janssen et al, ; Selenica et al, ). It has been described that CCL2 deficient expression in astrocytes leads to an impaired recruitment of peripheral immune cells and to a diminished reactivity of astrocytes and microglia, in a model of chronic EAE (Kim et al, ).…”

The role of chemokines and chemokine receptors in multiple sclerosis

“…CCL2, also known as MCP-1, is a potent chemokine for the recruitment process of macrophages, monocytes, activated T cells and NK cells to the CNS [47]. MCP is an important member of the CC subfamily.…”

“…Among MCPs, MCP-1was the first one to be discovered and is the most characteristic CC subclass chemokine in humans [15]. CCL2 can be produced by cells such as endothelial cells, astrocytes, macrophages and microglia [47]. One study showed that the efflux of CCL2 may be mediated by the astrocyte ABC transporters (MRP-1 and P-glycoprotein), thereby promoting the migration of immune cells across the brain endothelial cells, involved in the process of neuroinflammation [57].…”

Astrocyte-targeted production of interleukin-6 reduces astroglial and microglial activation in the cuprizone demyelination model: Implications for myelin clearance and oligodendrocyte maturation

“…In considering previous work reporting early upregulation of chemokines in the cuprizone model Janssen et al, 2015), we decided to perform the analysis after 1 and 4 weeks of the cuprizone treatment. In considering previous work reporting early upregulation of chemokines in the cuprizone model Janssen et al, 2015), we decided to perform the analysis after 1 and 4 weeks of the cuprizone treatment.…”