Yohei Ikezumi1, Tomomi Kondoh2, Yuji Matsumoto2, Naonori Kumagai2, Masahiro Kaneko3, Hiroya Hasegawa3, Takeshi Yamada3, Utako Kaneko3, David J Nikolic-Paterson4. 1. Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan. ikezumi@fujita-hu.ac.jp. 2. Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan. 3. Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan. 4. Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
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.
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.
Authors: Cintia S de Paiva; Claudia M Trujillo-Vargas; Laura Schaefer; Zhiyuan Yu; Robert A Britton; Stephen C Pflugfelder Journal: Front Immunol Date: 2021-07-19 Impact factor: 7.561