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

Background M1-type proinflammatory macrophages (M Phi) 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 M Phi 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). M Phi number and phenotype were assessed by immunofluorescence. In vitro studies used monocyte-derived M Phi 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+ M Phi infiltrate was comparable between N and S groups. However, N group had more M1 M Phi (CD68+ CD86+ cells) (p < 0.05) and fewer M2 M Phi (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 M Phi 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 M Phi was confirmed in biopsies from S group. Conclusions Initial steroid treatment induces M Phi 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 M Phi is a potential downside of steroid single therapy in LN.

Automated summary

Steroid treatment can lead to a shift in M1 proinflammatory macrophages towards an anti-inflammatory or profibrotic M2 phenotype in glomerular injury in lupus nephritis. While steroid treatment is effective in resolving M1-mediated injury, the promotion of fibrotic lesions via M2 macrophages may be a potential drawback of steroid monotherapy in LN.