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. 2014 Jun;176(3):341-50.
doi: 10.1111/cei.12287.

Endogenous interleukin (IL)-17A promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane

S A Summers  1 , D Odobasic, M B Khouri, O M Steinmetz, Y Yang, S R Holdsworth, A R Kitching
Affiliations

Endogenous interleukin (IL)-17A promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane (VSports注册入口)

S A Summers et al. Clin Exp Immunol. 2014 Jun.

Abstract

Interleukin (IL)-17A is increased both in serum and in kidney biopsies from patients with lupus nephritis, but direct evidence of pathogenicity is less well established. Administration of pristane to genetically intact mice results in the production of autoantibodies and proliferative glomerulonephritis, resembling human lupus nephritis. These studies sought to define the role of IL-17A in experimental lupus induced by pristane administration. Pristane was administered to wild-type (WT) and IL-17A(-/-) mice. Local and systemic immune responses were assessed after 6 days and 8 weeks, and autoimmunity, glomerular inflammation and renal injury were measured at 7 months. IL-17A production increased significantly 6 days after pristane injection, with innate immune cells, neutrophils (Ly6G(+)) and macrophages (F4/80(+)) being the predominant source of IL-17A. After 8 weeks, while systemic IL-17A was still readily detected in WT mice, the levels of proinflammatory cytokines, interferon (IFN)-γ and tumour necrosis factor (TNF) were diminished in the absence of endogenous IL-17A. Seven months after pristane treatment humoral autoimmunity was diminished in the absence of IL-17A, with decreased levels of immunoglobulin (Ig)G and anti-dsDNA antibodies. Renal inflammation and injury was less in the absence of IL-17A. Compared to WT mice, glomerular IgG, complement deposition, glomerular CD4(+) T cells and intrarenal expression of T helper type 1 (Th1)-associated proinflammatory mediators were decreased in IL-17A(-/-) mice VSports手机版. WT mice developed progressive proteinuria, but functional and histological renal injury was attenuated in the absence of IL-17A. Therefore, IL-17A is required for the full development of autoimmunity and lupus nephritis in experimental SLE, and early in the development of autoimmunity, innate immune cells produce IL-17A. .

Keywords: glomerulonephritis; interleukin 17A; lupus nephritis; pristane; systemic lupus erythematosus. V体育安卓版.

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Figures

Figure 1
Figure 1
Innate cells are major producers of interleukin (IL)-17A, 6 days after pristane treatment. (a) Compared to ‘untreated’ C57BL/6 wild-type (WT) mice that did not receive pristane (n = 6), administration of pristane to WT mice (n = 8) resulted in an increased number of intraperitoneal cells. (b) In addition, the number of cells within the peritoneum producing IL-17A increased after pristane treatment. Cells from untreated mice were pooled to ensure adequate numbers for analysis. (c) After pristane treatment, the majority of IL-17A-producing cells in the peritoneum were either CD11b+F4/80+ macrophages or CD11b+ lymphocyte antigen 6G (Ly6G+) neutrophils. CD4+ T cells, natural killer T cells and γδ T cells also produced IL-17A. (d) Representative fluorescence activated cell sorter (FACS) plots showing the proportion of peritoneal cells positive for IL-17A and F4/80+ or IL-17A and Ly-6G+ cells after pristane injection. *P < 0·05; **P < 0·01; ***P < 0·001; ****P < 0·0001.
Figure 2
Figure 2
Systemic (spleen) cytokine production in wild-type (WT) and interleukin (IL)-17A−/− mice, 8 weeks after pristane administration. Eight weeks after pristane injection we isolated and cultured splenocytes in media alone, with a Toll-like receptor (TLR)-4 ligand [highly purified lipopolysaccharide (LPS) 1 μg/ml] or a TLR-2 ligand, Pam3CSK4 (10 μg/ml) and measured cytokine production. Cultured splenocytes from pristane injected WT mice exhibited greater production of all cytokines compared to normal WT mice not given pristane (n = 5). (a) Systemic IL-17A, detected only at low levels in splenocytes cultures of WT mice not given pristane, was increased in pristine-treated WT mice (n = 6), and production increased further after culture with a TLR-4 or TLR-2 ligand. (b) Production of interferon (IFN)-γ and (c) tumour necrosis factor (TNF) were increased in WT mice compared to IL-17A−/− mice (n = 7) treated with pristane. (d) There was no difference in IL-2 production between WT and IL-17A−/− mice treated with pristane and (e) a trend towards increased IL-5 production was observed in IL-17A−/− mice. *P < 0·05; **P < 0·01; ***P < 0·001; ND = not detected.
Figure 3
Figure 3
Humoral autoimmunity is decreased in the absence of interleukin (IL)-17A. (a) Seven months after pristane treatment, levels of total immunoglobulin (Ig)G were decreased in IL-17A−/− mice (n = 7) compared to wild-type (WT) mice (n = 9) treated with pristane. (b) Similarly, titres of anti-dsDNA antibodies were decreased in IL-17A−/− mice. *P < 0·05; **P < 0·01.
Figure 4
Figure 4
Glomerular immunoglobulin (Ig)G and complement deposition is decreased in interleukin (IL)-17A−/− mice. (a) Glomerular IgG and C3 deposition was assessed 7 months after pristane treatment. Glomerular IgG was detectable in both wild-type (WT) and IL-17A−/− mice, but IL-17A−/− mice had less IgG within glomeruli. Representative photomicrographs (×400) of glomerular IgG deposition in WT and IL-17A−/− mice are shown. (b) Similarly, we found that C3 deposition was decreased in glomeruli of IL-17A−/− mice. Representative images of glomerular C3 deposition in WT and IL-17A−/− mice are shown. ****P < 0·0001. AU = arbitrary units.
Figure 5
Figure 5
Renal inflammation is diminished in the absence of interleukin (IL)-17A. (a) Seven months after pristane treatment intrarenal mRNA for the T cell transcription factors T-bet, retinoic acid-related orphan receptor gamma t (RORγt) and GATA-binding protein 3 (GATA-3) were decreased in IL-17A−/− mice. The reduction in forkhead box protein 3 (FoxP3) did not reach significance (P = 0·07). (b) mRNA for interferon (IFN)-γ and CXCL11, each a key T helper type 1 (Th1)-associated cytokine and chemokine were decreased in IL-17A−/− mice. (c) Representative images of single and multiple CD4+ T cells in glomeruli of wild-type (WT) mice. Glomerular CD4+ T cells were not observed regularly in IL-17A−/− mice. (d) Compared to WT mice, glomerular CD4+ T cell recruitment was decreased in IL-17A−/− mice. There were no differences in glomerular macrophage or neutrophil recruitment in WT or IL-17A−/− mice. *P < 0·05; **P < 0·01; ***P < 0·001; ****P < 0·0001. c/gcs = cells per glomerular cross-section.
Figure 6
Figure 6
Functional and histological renal injury is diminished in interleukin (IL)-17A−/− mice. (a) Following pristane injection there was a progressive increase in albuminuria. Compared to wild-type (WT, baseline n = 4, disease n = 9) mice treated with pristane, albuminuria was decreased in IL-17A−/− mice (baseline n = 5, disease n = 7). (b) Histological injury was also decreased in the absence of IL-17A, 7 months after pristane treatment. (c) Renal histological injury was attenuated in the absence of IL-17A. Periodic acid Schiff's (PAS) staining of representative images demonstrating glomerular injury with mesangial expansion and hypercellularity in WT mice are shown. In the lower panels, Masson trichrome staining shows accumulation of mesangial matrix and hypercellularity. Crescent formation (insert, WT) was uncommon in WT mice, but was absent in IL-17A−/− mice. *P < 0·05; ***P < 0·001.
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