B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression
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B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression. / Eckert, Nadine; Werth, Kathrin; Willenzon, Stefanie; Tan, Likai; Förster, Reinhold.
In: J LEUKOCYTE BIOL, Vol. 107, No. 6, 06.2020, p. 1155-1166.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression
AU - Eckert, Nadine
AU - Werth, Kathrin
AU - Willenzon, Stefanie
AU - Tan, Likai
AU - Förster, Reinhold
N1 - ©2019 Society for Leukocyte Biology.
PY - 2020/6
Y1 - 2020/6
N2 - The majority of genetically modified C57BL/6 mice contain congenic passenger DNA around the targeted gene locus as they were generated from 129-derived embryonic stem cells (ESCs) with subsequent backcrossing to the C57BL/6 genetic background. When studying the role of atypical chemokine receptor 4 (ACKR4) in the immune system, we realized that the two available Ackr4-deficient mouse strains (Ackr4-/- and Ackr4GFP/GFP ) show profoundly different phenotypes: Compared to wild-type and Ackr4GFP/GFP mice, Ackr4-/- mice show a strong accumulation of plasma blasts in mesenteric lymph node and spleen as well as increased B cell proliferation after in vitro activation. This phenotype was maintained after further backcrossing to C57BL/6 mice and was even present in heterozygous Ackr4+/- animals, suggesting that a gene variant on the targeted chromosome might cause this phenotype. Exome sequencing revealed that a region of approximately 20 Mbp around the Ackr4 locus on chromosome 9 still originates from the 129 background based on high variant density observed. In activated Ackr4-/- and Ackr4GFP/GFP B cells, transcripts of genes around the Ackr4 locus were equally deregulated compared to C57BL/6 B cells, whereas increased expression of IL-6 was selectively observed in B cells of Ackr4-/- mice. Because the gene encoding for IL-6 is placed on chromosome 5 these findings suggest that passenger DNA around the Ackr4 locus has an indirect effect on B cell activation and IL-6 production. Results of the present study should not only lead to the reinterpretation of data from earlier studies using Ackr4-/- mice but should remind the scientific community about the limitations of mouse models using mice created by gene-targeting of nonsyngeneic ESCs.
AB - The majority of genetically modified C57BL/6 mice contain congenic passenger DNA around the targeted gene locus as they were generated from 129-derived embryonic stem cells (ESCs) with subsequent backcrossing to the C57BL/6 genetic background. When studying the role of atypical chemokine receptor 4 (ACKR4) in the immune system, we realized that the two available Ackr4-deficient mouse strains (Ackr4-/- and Ackr4GFP/GFP ) show profoundly different phenotypes: Compared to wild-type and Ackr4GFP/GFP mice, Ackr4-/- mice show a strong accumulation of plasma blasts in mesenteric lymph node and spleen as well as increased B cell proliferation after in vitro activation. This phenotype was maintained after further backcrossing to C57BL/6 mice and was even present in heterozygous Ackr4+/- animals, suggesting that a gene variant on the targeted chromosome might cause this phenotype. Exome sequencing revealed that a region of approximately 20 Mbp around the Ackr4 locus on chromosome 9 still originates from the 129 background based on high variant density observed. In activated Ackr4-/- and Ackr4GFP/GFP B cells, transcripts of genes around the Ackr4 locus were equally deregulated compared to C57BL/6 B cells, whereas increased expression of IL-6 was selectively observed in B cells of Ackr4-/- mice. Because the gene encoding for IL-6 is placed on chromosome 5 these findings suggest that passenger DNA around the Ackr4 locus has an indirect effect on B cell activation and IL-6 production. Results of the present study should not only lead to the reinterpretation of data from earlier studies using Ackr4-/- mice but should remind the scientific community about the limitations of mouse models using mice created by gene-targeting of nonsyngeneic ESCs.
KW - Animals
KW - B-Lymphocytes/cytology
KW - Cell Proliferation
KW - Chromosomes, Mammalian/immunology
KW - Crosses, Genetic
KW - Embryonic Stem Cells/cytology
KW - Female
KW - Genes, Reporter
KW - Genetic Loci
KW - Green Fluorescent Proteins/genetics
KW - Heterozygote
KW - Homozygote
KW - Interleukin-6/genetics
KW - Lymph Nodes/cytology
KW - Lymphocyte Activation
KW - Male
KW - Mesentery/cytology
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Phenotype
KW - Receptors, CCR/deficiency
KW - Spleen/cytology
KW - Whole Exome Sequencing
U2 - 10.1002/JLB.2MA1119-300R
DO - 10.1002/JLB.2MA1119-300R
M3 - SCORING: Journal article
C2 - 31841228
VL - 107
SP - 1155
EP - 1166
JO - J LEUKOCYTE BIOL
JF - J LEUKOCYTE BIOL
SN - 0741-5400
IS - 6
ER -