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Steroid treatment promotes an M2 anti-inflammatory macrophage phenotype in childhood lupus nephritis

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Abstract

Background

M1-type proinflammatory macrophages (MΦ) promote glomerular injury in lupus nephritis (LN). However, whether this phenotype is altered by steroid therapy is unclear. Therefore, we investigated the effect of steroid treatment on MΦ phenotype in LN.

Methods

Patients with LN (7–18 years old) were divided into 2 groups: those with no treatment (N) before biopsy (n = 17) and those who underwent steroid (S) treatment (3–73 days) before biopsy (n = 15). MΦ number and phenotype were assessed by immunofluorescence. In vitro studies used monocyte-derived MΦ from healthy volunteers.

Results

Age at biopsy, urine findings, and kidney function (eGFR) were comparable between the two groups. Biopsies in N group had higher levels of active lesions such as endocapillary hypercellularity, necrosis, and cellular crescent formation (p < 0.05). The total CD68+ MΦ infiltrate was comparable between N and S groups. However, N group had more M1 MΦ (CD68+ CD86+ cells) (p < 0.05) and fewer M2 MΦ (CD68+ CD163+ cells) (p < 0.05), giving a 6-fold increase in the M2/M1 ratio in S vs. N groups. Dexamethasone treatment of cultured MΦ induced upregulation of CD163 expression, increased production of anti-inflammatory (IL-10, IL-19) and profibrotic factors (FGF-22, PDGF), and upregulated the scavenger receptor, stabilin-1. Upregulation of stabilin-1 in CD163+ M2 MΦ was confirmed in biopsies from S group.

Conclusions

Initial steroid treatment induces MΦ phenotypic change from proinflammatory M1 to anti-inflammatory or profibrotic M2 in LN with acute/active lesions. Although steroid treatment is effective for resolution of M1-medated injury, promotion of fibrotic lesions via M2 MΦ is a potential downside of steroid single therapy in LN.

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Funding

This work was supported by JSPS KAKENHI grant number JP20K08219 to Y.I.

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Authors and Affiliations

  1. Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan

    Yohei Ikezumi, Tomomi Kondoh, Yuji Matsumoto & Naonori Kumagai

  2. Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan

    Masahiro Kaneko, Hiroya Hasegawa, Takeshi Yamada & Utako Kaneko

  3. Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

    David J. Nikolic-Paterson

Authors
  1. Yohei Ikezumi
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  2. Tomomi Kondoh
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  3. Yuji Matsumoto
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  4. Naonori Kumagai
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  5. Masahiro Kaneko
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  6. Hiroya Hasegawa
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  7. Takeshi Yamada
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  8. Utako Kaneko
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  9. David J. Nikolic-Paterson
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Contributions

Y.I. and D.J.N-P. designed the study. Y.I., T.K., Y.M., N.K., M.K., H.H., T.Y., and U.K. were involved in the acquisition of data. Y.I., N.K., and D.J.N-P. contributed to analysis and interpretation of data. Y.I. and D.J.N-P. provided writing or revision of the manuscript. All authors approved the final version.

Corresponding author

Correspondence to Yohei Ikezumi.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number HM19-055)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Supplemental Figure 1

Representative photomicrographs of kidney lesions in lupus nephritis (LN). (a) PAS staining shows a glomerulus with endocapillary hypercellularity ands a cellular crescent (arrow head); (b) HE staining shows a glomerulus with endocapillary hypercellularity and wire loops (arrow head). The same biopsy is stained with PAS (c) or Masson trichrome (d), to show glomeruli with segmental sclerosis or fibrous adhesion (arrow head), and interstitial fibrosis. (PPTX 2345 kb)

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Ikezumi, Y., Kondoh, T., Matsumoto, Y. et al. Steroid treatment promotes an M2 anti-inflammatory macrophage phenotype in childhood lupus nephritis. Pediatr Nephrol 36, 349–359 (2021). https://doi.org/10.1007/s00467-020-04734-w

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  • DOI: https://doi.org/10.1007/s00467-020-04734-w

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