N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody-induced arthritis
March
N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody- induced arthritis
Ji Young Kim 0 1
Kyu Lim 1
Kyung Hee Kim 1
Jin Hyun Kim 0 1
Jin Sun Choi 0 1
Seung- Cheol Shim 0 1
0 Division of Rheumatology, Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital , Daejeon , Republic of Korea, 2 Department of Biochemistry and Cancer Research Institute, College of Medicine, Chungnam National University , Daejeon , Republic of Korea, 3 Department of Pathology, Cancer Research Institute, College of Medicine, Chungnam National University , Daejeon , Republic of Korea
1 Editor: Hossam M. Ashour, University of South Florida St Petersburg , UNITED STATES
-
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: Ji Young Kim was supported by the Basic
Science Research Program through the National
Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science, and Technology
(MEST) under Grant number:
NRF2013R1A1A2057950 (http://www.nrf.re.kr/nrf_tot_
cms/index.jsp). The funder had no role in study
N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and were considered
useful for the treatment of rheumatoid arthritis (RA). Recently, several studies suggested
that n-3 PUFAs attenuated arthritis in animal model and human, however the mechanism is
still unclear. Interleukin 17 (IL-17) is a pro-inflammatory cytokine mainly produced by T
helper 17 (Th17) cells which cause tissue inflammation and bone erosion leading to joint
destruction. In contrast, regulatory T (Treg) cells down-regulate various immune responses
by suppression of naïve T cells. The imbalance between Th17 cells and Tregs cell is
important for the pathogenesis of RA. Here, we investigated whether n-3 PUFAs attenuate
arthritis in collagen antibody-induced arthritis (CAIA) model. We used fat-1 transgenic mice
expressing the Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase
that converts n-6 to n-3 fatty acids, leading to abundant n-3 fatty acids without the need of a
dietary n-3 supply. Clinical arthritis score was significantly attenuated in fat-1 mice
compared to wild type (WT) mice on day 7 (1.6±1.8, p = 0.012) and day 9 (1.5±1.6, p = 0.003).
Ankle thickness also decreased significantly in fat-1 mice compared to WT mice (1.82±0.11,
p = 0.008). The pathologic finding showed that inflammatory cell infiltration and bone
destruction were reduced in fat-1 mice compared to WT. The expression levels of IL-17 and
related cytokines including IL-6 and IL-23 decreased in the spleen and ankle joint tissue of
fat-1 mice compared to WT mice. Furthermore, Treg cells were expanded in the spleen of
fat-1 mice and Treg cell differentiation was significantly higher in fat-1 mice than in wild type
(p = 0.038). These data suggest that n-3 PUFAs could attenuate arthritis through increasing
the expression of FoxP3 and the differentiation of Treg, while reducing IL-17 production.
Therefore, dietary supplementation of n-3 PUFAs could have a therapeutic potential for the
treatment of RA.
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation
of a joint synovium, leading to progressive bone and cartilage destruction [
1
]. Recently, T
helper 17 (Th17) cells have been suggested to play key roles in RA induction and maintenance.
Th17 cells are pro-inflammatory cells, which produce interleukin 17 (IL-17) and
differentiation is dependent on IL-6, IL-23 and TGF-β [
2,3
]. IL-17 is raised in synovial fluids of RA
patients and in inflamed joints of experimental induced arthritis models. IL-17 induces
inflammatory cell infiltration into the synovium and tissue inflammation, leading into bone
resorption and erosion [4]. In contrast CD4+CD25+Foxp3+ regulatory T cell (Treg) regulates the
immune response to keep peripheral self-tolerance [
5
]. Th17 and Treg cells antagonize each
other's function, the imbalance between Th17 and Treg cells may be important in the
development of RA.
N-3 polyunsaturated fatty acid (n-3 PUFA) has shown anti-inflammatory effect through
immune cell inhibition [6±8]. N-3 PUFAs are primarily obtained from the diet, only low
conversion of α-linolenic acid (ALA) to eicosapentanoic acid (EPA) and docosahexaenoic acid
(DHA) [
9
]. Recently, experimental animal studies reported that n-3 PUFAs suppress
inflammatory cytokine synthesis [
10
]. In addition, n-3 PUFAs reduced the number and
differentiation of pro-inflammatory Th17 cells [7±8, 11] and increased number of Treg cells in vivo [
12
].
A fat-1 transgenic mouse expresses the Caenorhabditis elegans fat-1 gene encoding an n-3
fatty acid desaturase that converts n-6 to n-3 fatty acids (which is absent in mammals), leading
to abundant n-3 fatty acids with reduced levels of n-6 fatty acid (...truncated)