Infiltration of Hematogenous Lineage Cells Into the Demyelinating Central Nervous System of Twitcher Mice

Abstract

Infiltration of hematogenous lineage cells into the central nervous system (CNS) was investigated in the twitcher mouse, a murine model of globoid cell leukodystrophy in human. The hematogenous cells were selectively labeled following intraperitoneal injection of rhodamine isothiocyanate (RhIc). The frequency of detecting Rhlc-labeled cells (Rhlc+ cells) in the twitcher CNS varied with age. RhIc+ cells were hardly detected when injection was made prior to the postnatal day (PND) 30. The number of Rhlc' cells increased thereafter peaked at PND 35-38 and declined drastically at PND 40-45. The majority of RhIc+ cells were distributed in white matter of the CNS that correlated well with the areas of demyelination and of increased microglia/macrophage population described in our earlier studies. Almost all Rhlc+ cells were double-labeled with antibody for Mac-1 and also with MHC class II. Some small cells double-labeled with RhIc and antibodies for CD4, CD8, or IL-2R were also identified. By RT-PCR, the expression of monocyte chemoattractant protein- (MCP-1) mRNA increased drastically at PND 30, peaked at PND 35, and decreased gradually after PND 40. This pattern of mRNA changes correlated well with the dynamic pattern of the infiltration of hematogenous cells into the CNS, suggesting a role of chemokine(s) in the cellular infiltration in the twitcher brain. The expression of IL-10 mRNA also increased gradually. IL-10 is a cytokine inhibitory factor and a major regulator in suppressing the inflammatory response. Thus, our results indicated that hematogenous lineage cells infiltrated in the CNS of twitcher mice, and that MCP-1 and IL-10 may play an important role in regulating the cellular recruitment.

Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology

“…This procedure has been implemented with promising results in other animal models of LSDs. 23,[55][56][57][58] It is becoming increasingly clear, however, that individual LSDs respond differently to the same therapeutic paradigm, most likely because of the nature of the enzyme defect, the accumulated products, and their combined effect on cell metabolism.…”

“…[11][12][13][14][15] In the CNS, chemokines are expressed constitutively at low or negligible levels in astrocytes and microglia, but their expression is rapidly induced by neuroinflammatory conditions [16][17][18] and is mediated by several proinflammatory cytokines (eg, tumor necrosis factor ␣ [TNF-␣], interferon ␥ [IFN-␥], and tumor growth factor ␤1 [TGF-␤1]). [19][20][21][22] CNS inflammation occurs in several neurodegenerative conditions, including those associated with a lysosomal storage disease (LSD), [23][24] and is likely responsible for the recruitment of monocytes and macrophages from peripheral blood. In the murine model of the LSD, G M2 -gangliosidosis recruitment of macrophages into the CNS is mediated by the chemokine macrophage inflammatory protein 1-␣ (MIP-1␣) and has been implicated in the pathogenesis of this disease.…”

Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

“…Neuroinflammation is implicated in the progressive nature of several neurodegenerative diseases and is described in almost all LSDs with neurological involvement (21)(22)(23)(24)(25)(26)(27). However, it is still unclear whether macrophage and astrocyte activation in LSDs is triggered by their intracellular storage or represents a response to neuronal damage.…”

Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination intwitcher

“…The absence of MHC class II molecules reduces CNS demyelination and microglial/macrophage infiltration in the twitcher brain (Matsushima et al, 1994). It has also been reported that there is expression of proinflammatory molecules, such as interleukin-6 (IL-6), tumor necrosis factor ␣ (TNF␣) (LeVine and Brown, 1997), monocyte chemoattractant protein-1, interferon-induced protein-10, macrophage inflammatory protein-1␣ (MIP-1␣), MIP-1␤, and RANTES (regulated on activation normal T-cell expressed and secreted) (Wu et al, 2000) in twitcher. Furthermore, we recently reported that TNF␣ expression increased with the progression of demyelination in twitcher and that a TNF␣ inhibitor suppresses such demyelination (Kagitani-Shimono et al, 2005).…”