Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-kappaB and Akt.
Chemotactic factors known as chemokines play an important role in the pathogenesis of multiple sclerosis (MS). Transgenic expression of TNFalpha in the central nervous system (CNS) leads to the development of a demyelinating phenotype (TNFalpha-induced demyelination; TID) that is highly reminiscent of MS. Little is known about the role of chemokines in TID but insights derived from studying this model might extend our current understanding of MS pathogenesis and complement data derived from the classic autoimmune encephalomyelitis (EAE) model system. Here we show that in TID, chemokines and their receptors were significantly increased during the acute phases of disease. Notably, the CCL2 (MCP-1)-CCR2 axis and the closely related ligand-receptor pair CCR1-CCL3 (MIP-1alpha) were among the most up-regulated during disease. On the other hand, receptors like CCR3 and CCR4 were not elevated. This significant increase in the levels of chemokines/receptors correlated with robust immune infiltration of the CNS by inflammatory cells, i.e., macrophages, and immune cells particularly T and B cells. Immunostaining and confocal microscopy, along with in vitro studies revealed that astrocytes were a major source of locally produced chemokines and expressed functional chemokine receptors such as CCR2. Using an in vitro system we demonstrate that expression of CCR2 was functional in astrocytes and that signaling via this receptor lead to activation of NF-kB and Akt and was associated with increased astrocyte survival. Collectively, our data suggests that transgenic murine models of MS are useful to dissect mechanisms of disease and that in these models, up-regulation of chemokines and their receptors may be key determinants in TID.
Quinones
Marlon P
MP
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA.
Kalkonde
Yogeshwar
Y
Estrada
Carlos A
CA
Jimenez
Fabio
F
Ramirez
Robert
R
Mahimainathan
Lenin
L
Mummidi
Srinivas
S
Choudhury
Goutam G
GG
Martinez
Hernan
H
Adams
Lisa
L
Mack
Matthias
M
Reddick
Robert L
RL
Maffi
Shivani
S
Haralambous
Sylva
S
Probert
Lesley
L
Ahuja
Sunil K
SK
Ahuja
Seema S
SS
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002452:Cell Count / Q000379:methods; D018932:Chemokine CCL2 / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054390:Receptors, CCR2 / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D015398:Signal Transduction / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase
D018932:Chemokine CCL2; D018925:Chemokines; D005904:Glial Fibrillary Acidic Protein; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D054390:Receptors, CCR2; D047888:Receptors, Tumor Necrosis Factor, Type I; D013936:Thymidine; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C515335:Ccr2 protein, mouse; C506236:Tnfrsf1a protein, mouse