Bone marrow deficiency of MCPIP1 results in severe multi-organ inflammation but diminishes atherogenesis in hyperlipidemic mice.
OBJECTIVE
MCPIP1 is a newly identified protein that profoundly impacts immunity and inflammation. We aim to test if MCPIP1 deficiency in hematopoietic cells results in systemic inflammation and accelerates atherogenesis in mice.


RESULTS
After lethally irradiated, LDLR(-/-) mice were transplanted with bone marrow cells from either wild-type or MCPIP1(-/-) mice. These chimeric mice were fed a western-type diet for 7 weeks. We found that bone marrow MCPIP1(-/-) mice displayed a phenotype similar to that of whole body MCPIP1(-/-) mice, with severe systemic and multi-organ inflammation. However, MCPIP1(-/-) bone marrow recipients developed >10-fold less atherosclerotic lesions in the proximal aorta than WT bone marrow recipients, and essentially no lesions in en face aorta. The diminishment in atherosclerosis in bone marrow MCPIP1(-/-) mice may be partially attributed to the slight decrease in their plasma lipids. Flow cytometric analysis of splenocytes showed that bone marrow MCPIP1(-/-) mice contained reduced numbers of T cells and B cells, but increased numbers of regulatory T cells, Th17 cells, CD11b+/Gr1+ cells and CD11b+/Ly6C(low) cells. This overall anti-atherogenic leukocyte profile may also contribute to the reduced atherogenesis. We also examined the cholesterol efflux capability of MCPIP1 deficient macrophages, and found that MCPIP1 deficiency increased cholesterol efflux to apoAI and HDL, due to increased protein levels of ABCA1 and ABCG1.


CONCLUSIONS
Hematopoietic deficiency of MCPIP1 resulted in severe systemic and multi-organ inflammation but paradoxically diminished atherogenesis in mice. The reduced atheroegensis may be explained by the decreased plasma cholesterol levels, the anti-atherogenic leukocyte profile, as well as enhanced cholesterol efflux capability. This study suggests that, while atherosclerosis is a chronic inflammatory disease, the mechanisms underlying atherogenesis-associated inflammation in arterial wall versus the inflammation in solid organs may be substantially different.
Department of Nutrition and Food Hygiene, the Fourth Military Medical University, Xi'an, Shaanxi, China ; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
Fang
F
Yu
Fen
F
Du
Yuzhen
Y
Wang
Shengping
S
Huang
Ruidong
R
Miao
Amy S
AS
Major
E Angela
EA
Murphy
Mingui
M
Fu
Daping
D
Fan
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D005260:Female; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012260:Ribonucleases / Q000172:deficiency* / Q000235:genetics
D012260:Ribonucleases; C541320:Zc3h12a protein, mouse