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IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis

Hou, Yuzhu, Zhu, Linnan, Tian, Hongling, Sun, Hai-Xi, Wang, Ruoyu, Zhang, Lianfeng, Zhao, Yong·2018·Protein & Cell
DOI 10.1007/s13238-018-0505-zPMC PMC6251802
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Abstract

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.

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Figure 1 Cytokine expression of macrophages stimulated with different cytokines. (A) The freshly isolated peritoneal macrophages (PEMs) were stimulated with different cytokines and LPS for 48 h. Cytokine mRNA expression were detected by real-time PCR. (B) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in PEMs treated with different doses of IL-23. (C) Concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in the media of PEMs after IL-23 treatment for 48 h. (D) The percentages of IL-17A+ cells in F4/80+ PEMs were detected by a flow cytometry. (E) The percentages of IFN-γ+ cells in F4/80+ PEMs treated with IL-23. (F) The expression of IL-17A and IFN-γ in PEMs were determined using two-photon microscope. Data were shown as mean ± SD (n = 3). **P < 0.01, ***P < 0.001 compared with the control
Figure 1 Cytokine expression of macrophages stimulated with different cytokines. (A) The freshly isolated peritoneal macrophages (PEMs) were stimulated with different cytokines and LPS for 48 h. Cytokine mRNA expression were detected by real-time PCR. (B) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in PEMs treated with different doses of IL-23. (C) Concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in the media of PEMs after IL-23 treatment for 48 h. (D) The percentages of IL-17A+ cells in F4/80+ PEMs were detected by a flow cytometry. (E) The percentages of IFN-γ+ cells in F4/80+ PEMs treated with IL-23. (F) The expression of IL-17A and IFN-γ in PEMs were determined using two-photon microscope. Data were shown as mean ± SD (n = 3). **P < 0.01, ***P < 0.001 compared with the controlCC BY · PubMed Central
Figure 2 IL-23-treated macrophages produce a distinctive panel of cytokines. (A) The mRNA expression of M1 and M2 marker molecules and Th17-cytokines in macrophages were detected by real-time PCR. (B) NO concentrations in M0, M1, M2 and M(IL-23) macrophage culture medium. (C) TNF-α concentrations in the culture medium. (D) Arginase activity of M0, M1, M2 and M(IL-23) macrophages was assayed. (E) Concentrations of IL-17A, IL-17F and IL-22 in the culture medium. (F) Representative flow cytometry results (left) and summarized percentages (right) of TNF-α+, iNOS+ and IL-17A+ cells in the F4/80+ macrophages. (G) The expression of TNF-α, IL-17A and IFN-γ in M0, M1 and M(IL-23) were determined using a two-photon microscope. Data were shown as mean ± SD (n = 4). **P < 0.01, ***P < 0.001 compared with the control
Figure 2 IL-23-treated macrophages produce a distinctive panel of cytokines. (A) The mRNA expression of M1 and M2 marker molecules and Th17-cytokines in macrophages were detected by real-time PCR. (B) NO concentrations in M0, M1, M2 and M(IL-23) macrophage culture medium. (C) TNF-α concentrations in the culture medium. (D) Arginase activity of M0, M1, M2 and M(IL-23) macrophages was assayed. (E) Concentrations of IL-17A, IL-17F and IL-22 in the culture medium. (F) Representative flow cytometry results (left) and summarized percentages (right) of TNF-α+, iNOS+ and IL-17A+ cells in the F4/80+ macrophages. (G) The expression of TNF-α, IL-17A and IFN-γ in M0, M1 and M(IL-23) were determined using a two-photon microscope. Data were shown as mean ± SD (n = 4). **P < 0.01, ***P < 0.001 compared with the controlCC BY · PubMed Central
Figure 3 IL-23-treated macrophages display a distinctive gene expression profile. (A) Heatmap diagram summarizing gene expression in M0, M1, M2 and M(IL-23) cells. Relative gene expression was depicted according to the color scale shown below the cluster. (B) Venn diagram of up-regulated (top) and down-regulated (bottom) genes in M1, M2 and M(IL-23) compared with M0 cells. (C) Heatmap diagram summarizing cytokines and chemokines expression in M0, M1, M2 and M(IL-23) macrophages. Relative gene expression was depicted according to the color scale. (D) Representative staining of I-Ab, and CD206 on M0, M1, M2 and M(IL-23) cells. (E) Percentages of I-Ab+, and CD206+ cells in F4/80+ M0, M1 and M(IL-23) cells. Data were shown as mean ± SD (n = 3). ***P < 0.001 for comparisons between the indicated groups
Figure 3 IL-23-treated macrophages display a distinctive gene expression profile. (A) Heatmap diagram summarizing gene expression in M0, M1, M2 and M(IL-23) cells. Relative gene expression was depicted according to the color scale shown below the cluster. (B) Venn diagram of up-regulated (top) and down-regulated (bottom) genes in M1, M2 and M(IL-23) compared with M0 cells. (C) Heatmap diagram summarizing cytokines and chemokines expression in M0, M1, M2 and M(IL-23) macrophages. Relative gene expression was depicted according to the color scale. (D) Representative staining of I-Ab, and CD206 on M0, M1, M2 and M(IL-23) cells. (E) Percentages of I-Ab+, and CD206+ cells in F4/80+ M0, M1 and M(IL-23) cells. Data were shown as mean ± SD (n = 3). ***P < 0.001 for comparisons between the indicated groupsCC BY · PubMed Central
Figure 4 M(IL-23), M1 and M2 polarizations are reciprocally regulated. (A) The mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in M0, M1, M(IL-23) and IL-23-treated M1 cells. (B) Concentrations of IL-17A, IL-17F and IL-22 cytokines in culture media of M0, M1, M(IL-23) and IL-23-treated M1 cells. (C) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in resting and TG-recruited peritoneal macrophages treated with or without IL-23 for 48 h. (D) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in M0, M2, M(IL-23) and IL-23-treated M2 cells. (E) Concentrations of IL-17A, IL-17F and IL-22 in the culture media of M0, M2, M(IL-23) and IL-23-treated M2 cells. Data were shown as mean ± SD (n = 3). ***P < 0.001 for comparisons between the indicated groups
Figure 4 M(IL-23), M1 and M2 polarizations are reciprocally regulated. (A) The mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in M0, M1, M(IL-23) and IL-23-treated M1 cells. (B) Concentrations of IL-17A, IL-17F and IL-22 cytokines in culture media of M0, M1, M(IL-23) and IL-23-treated M1 cells. (C) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in resting and TG-recruited peritoneal macrophages treated with or without IL-23 for 48 h. (D) mRNA expression of IL-17A, IL-17F, IL-22 and IFN-γ in M0, M2, M(IL-23) and IL-23-treated M2 cells. (E) Concentrations of IL-17A, IL-17F and IL-22 in the culture media of M0, M2, M(IL-23) and IL-23-treated M2 cells. Data were shown as mean ± SD (n = 3). ***P < 0.001 for comparisons between the indicated groupsCC BY · PubMed Central
Figure 5 The involvement of STAT3-RORγT and T-bet in M(IL-23) polarization. (A) The phosphorylation state of STAT3 in PEMs. (B) The protein concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in culture media of macrophages treated with IL-23 and/or STAT3 inhibitor NSC74859. (C) The expression of RORγT, RORα, IRF4 and BATF in macrophages. (D) The mRNA expression of RORγT, RORα, IRF4 and BATF in macrophages. (E) RORγT expression in macrophages treated with or without IL-23 and/or NSC74859. (F) Protein concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in culture media of macrophages. T-bet protein (G) and mRNA (H) expression in macrophages treated with IL-23. (I) The decreased expression of IFN-γ in T-bet-deficient macrophages. Data were shown as mean ± SD (n = 3). *P < 0.05, ***P < 0.001
Figure 5 The involvement of STAT3-RORγT and T-bet in M(IL-23) polarization. (A) The phosphorylation state of STAT3 in PEMs. (B) The protein concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in culture media of macrophages treated with IL-23 and/or STAT3 inhibitor NSC74859. (C) The expression of RORγT, RORα, IRF4 and BATF in macrophages. (D) The mRNA expression of RORγT, RORα, IRF4 and BATF in macrophages. (E) RORγT expression in macrophages treated with or without IL-23 and/or NSC74859. (F) Protein concentrations of IL-17A, IL-17F, IL-22 and IFN-γ in culture media of macrophages. T-bet protein (G) and mRNA (H) expression in macrophages treated with IL-23. (I) The decreased expression of IFN-γ in T-bet-deficient macrophages. Data were shown as mean ± SD (n = 3). *P < 0.05, ***P < 0.001CC BY · PubMed Central
Figure 6 M(IL-23) promoted the pathogenesis in imiquimod-induced psoriasis mice. (A) mRNA expression of IL-17A and IL-22 in the sorted F4/80+ macrophages of skin tissue. (B) We used a suboptimal dose of IMQ (35 mg/day), and a standard dose of IMQ (70 mg/day) was used as a positive control (IMQ, high dose). The IMQ (35 mg/day)-treated mice were transferred with PBS, 1 × 106 M0 or M(IL-23) macrophages. Body weight loss was shown. (C) H&E staining of the skin tissues. Scaling score (D), erythema score (E), hardness score (F), skin thickness (G) and cumulative score (H) of mice. (I) mRNA expression of IL-17A, IL-17F, and IL-22 in skin tissues. Data were shown as mean ± SD (n = 8). **P < 0.01, ***P < 0.001 for comparisons between the indicated groups
Figure 6 M(IL-23) promoted the pathogenesis in imiquimod-induced psoriasis mice. (A) mRNA expression of IL-17A and IL-22 in the sorted F4/80+ macrophages of skin tissue. (B) We used a suboptimal dose of IMQ (35 mg/day), and a standard dose of IMQ (70 mg/day) was used as a positive control (IMQ, high dose). The IMQ (35 mg/day)-treated mice were transferred with PBS, 1 × 106 M0 or M(IL-23) macrophages. Body weight loss was shown. (C) H&E staining of the skin tissues. Scaling score (D), erythema score (E), hardness score (F), skin thickness (G) and cumulative score (H) of mice. (I) mRNA expression of IL-17A, IL-17F, and IL-22 in skin tissues. Data were shown as mean ± SD (n = 8). **P < 0.01, ***P < 0.001 for comparisons between the indicated groupsCC BY · PubMed Central

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Metadata

Authors
Hou, Y., Zhu, L., Tian, H., Sun, H.-X., Wang, R., Zhang, L., & Zhao, Y.
Affiliations
  • State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences , 100101, Beijing , China
  • Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University , 116001, Dalian , China
  • Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College , 100021, Beijing , China
Venue
Protein & Cell
Publisher
Oxford University Press (OUP)
Published
2018-03-05
Volume
9
Issue
12
Pages
1027-1038
ISSN
  • 1674-800X
  • 1674-8018
DOI
10.1007/s13238-018-0505-z
PMC
PMC6251802
Cited by
179
References
7
Language
en
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