Abstract
Monocytes’ plasticity has an important role in the development of rheumatoid arthritis (RA), an autoimmune disease exhibiting greater prevalence in women. Contribution of this phenomenon to sex bias in RA severity was investigated in rat collagen-induced arthritis (CIA) model of RA. The greater severity of CIA in females (exhibiting signs of bone resorption) was accompanied by the higher blood level of advanced oxidation protein products and a more pro-oxidant profile. Consistently, in females, the greater density of giant multinuclear cells (monocytes/macrophages and osteoclasts) in inflamed joint tissue was found. This correlated with the higher frequencies of CCR2- and CX3CR1- expressing cells (precursors of inflammatory monocytes/macrophages and osteoclasts) among CD11b+ splenocytes. This in conjunction with the enhanced migratory capacity of CD11b+ monocytic cells in females compared with males could be linked with the higher frequencies of CCR2+CX3CR1-CD43lowCD11b+ and CCR2-CX3CR1+CD43hiCD11b+ cells (corresponding to “classical” and “non-classical” monocytes, respectively) and the greater density of CD68+ cells (monocytes/macrophages and osteoclast precursors/osteoclasts) in blood and inflamed paws from female rats, respectively. Consistently, the higher levels of GM-CSF, TNF-α and IL-6, IL-1β (driving Th17 cell differentiation), and IL-17 followed by the lower level of IL-10 were measured in inflamed paw cultures from female compared with male rats. To the greater IL-17 production (associated with enhanced monocyte immigration and differentiation into osteoclasts) most likely contributed augmented Th17 cell generation in the lymph nodes draining arthritic joints from female compared with male rats. Overall, the study suggests the sex-specific contribution of monocytic lineage cells to CIA, and possibly RA development.
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The study was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grants no 451-03-68/2020-14/200161 and 451-03-68/2020-14/200007).
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Conception and design of the study: M.D. and G.L. Acquisition, analysis, and interpretation of data: N.A-R., D.K., B.B., I.P., M.N-A., J.K-S., L.S., J.S., and M.D. Drafting the manuscript: N.A-R. and M.D. Critical revision of the manuscript: G.L.
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Supplementary Fig. 1
Sex differences in the clinical and histological presentation of CIA. (a) A line graph indicates daily arthritic score (mean ± SEM) from the 12th to the 39th day post-immunization (d.p.i.) in male (n = 9) and female (n = 10) CIA rats. Mann–Whitney U test: * p ≤ 0.05, from the 17th to the 39th d.p.i. (b) Line graph indicates daily arthritic score (mean ± SEM) from the 13th to the 21st day post-immunization (d.p.i.) in male and female CIA rats. Mann–Whitney U test: n = 8 rats/sex. * p ≤ 0.05. Photographs show representative arthritic joints (arrows) of hind paws from male and female CIA rats. (c) Photomicrographs of HE-stained sections of paraffin-embedded joints from male and female CIA rats show replacement of the normal bone marrow cell populations by inflammatory cells. In females, numerous multinuclear giant cells (red arrows) are present as opposed to male CIA rats. Original magnification × 400. The bar indicates 100 μm (PNG 2723 kb)
Supplementary Fig. 2
Fluorescence minus one controls for flow cytometry analysis of CD11b/CCR2/CX3CR1 staining of splenocytes. For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without anti-CX3CR1 or anti-CCR2 Abs within CD11b+ splenocytes (gated as shown in Fig. 3) isolated from CIA rats on the 21st day post-immunization (PNG 98 kb).
Supplementary Fig. 3
Fluorescence minus one controls for flow cytometry analysis of CD11b/CD43/CCR2/CX3CR1 staining of peripheral blood cells. For setting cutoff boundaries, gates were controlled using fluorescence minus one (FMO) controls obtained by omitting a single antibody from the labeling antibody cocktail. Flow cytometry dot plots represent FMO controls without (upper) CD43 mAb within CD11b+ peripheral blood cells (gated as shown in Fig. 4a) and (lower) anti-CX3CR1 or anti-CCR2 Abs within CD11b+CD43+ peripheral blood cells isolated from CIA rats on the 21st day post-immunization (PNG 157 kb).
Supplementary Fig. 4
Sex differences in the activation of Th cells, Th17 cell function, and frequency of CD40+CD11b+ antigen presenting cells in draining lymph nodes from CIA rats, popliteal draining lymph nodes (DLNs) were retrieved from male and female CIA rats on the 21st day post-immunization. (a) Scatter plots with bar indicate the frequencies of activated Th cells (CD25+Foxp3-CD4+) and Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats and the concentration of IL-17 in supernatants of collagen type II-stimulated and unstimulated (medium) DLN cell cultures from male and female rats (see MATERIAL AND METHODS). Linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of Th17 cells (IL-17+CD4+TCRαβ+) in DLNs from CIA rats. Pearson’s r value is shown in the graph. (b) Representative flow cytometry dot plots show (upper) CD11b staining and (lower) CD40 vs CD11b staining of DLN cells from male and female rats. Number indicates percent in the region. Scatter plots with bar indicate the frequency and the number of (upper) CD11b+ cells and (lower) CD40+CD11b+ cells in DLNs of male and female rats. The Number indicates percent in the region. Results are expressed as mean ± SEM. (c) The linear graph shows the correlation between the frequency of activated Th cells (CD25+Foxp3-CD4+) and the frequency of CD40+CD11b+ cells in DLNs from CIA rats. Pearson’s r value is shown in the graph. n = 8 rats/sex. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001 (PNG 590 kb).
Supplementary Fig. 5
Gating strategy for activated Th cells and Th17 cells, popliteal draining lymph nodes (DLNs) were retrieved from CIA rats on the 21st day post-immunization. Flow cytometry dot plots show gating strategy for (a) activated The cells (CD25+Foxp3-CD4+) and (b) Th17 cells (IL-17+CD4+TCRαβ+) (PNG 101 kb).
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Dimitrijević, M., Arsenović-Ranin, N., Bufan, B. et al. Sex-Based Differences in Monocytic Lineage Cells Contribute to More Severe Collagen-Induced Arthritis in Female Rats Compared with Male Rats. Inflammation 43, 2312–2331 (2020). https://doi.org/10.1007/s10753-020-01302-0
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DOI: https://doi.org/10.1007/s10753-020-01302-0