Identification of gene regions regulating inflammatory microglial response in the rat CNS after nerve injury.
Local CNS inflammation takes place in many neurological disorders and is important for autoimmune neuroinflammation. Microglial activation is strain-dependent in rats and differential MHC class II expression is influenced by variations in the Mhc2ta gene. Despite sharing Mhc2ta and MHC class II alleles, BN and LEW.1N rats differ in MHC class II expression after ventral root avulsion (VRA). We studied MHC class II expression and glial activation markers in BN rats after VRA. Our results demonstrate that MHC class II expression originates from a subpopulation of IBA1(+), ED1(-), and ED2(-) microglia. We subsequently performed a genome-wide linkage scan in an F2(BNxLEW.1N) population, to investigate gene regions regulating this inflammatory response. Alongside MHC class II, we studied the expression of MHC class I, co-stimulatory molecules, complement components, microglial markers and Il1b. MHC class II and other transcripts were commonly regulated by gene regions on chromosomes 1 and 7. Furthermore, a common region on chromosome 10 regulated expression of complement and co-stimulatory molecules, while a region on chromosome 11 regulated MHC class I. We also detected epistatic interactions in the regulation of the inflammatory process. These results reveal the complex regulation of CNS inflammation by several gene regions, which may have relevance for disease.
Diez
Margarita
M
Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, S171 76 Stockholm, Sweden. Margarita.Diez@ki.se
Abdelmagid
Nada
N
Harnesk
Karin
K
Ström
Mikael
M
Lidman
Olle
O
Swanberg
Maria
M
Lindblom
Rickard
R
Al-Nimer
Faiez
F
Jagodic
Maja
M
Olsson
Tomas
T
Piehl
Fredrik
F
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D002874:Chromosome Mapping; D004660:Encephalitis / Q000276:immunology*; D004843:Epistasis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D008040:Genetic Linkage; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D017628:Microglia / Q000502:physiology*; D040641:Quantitative Trait Loci; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C045084:invariant chain