IL-10/TGF-β–Modified Macrophages Induce Regulatory T Cells and Protect against Adriamycin Nephrosis

Abstract

IL-10/TGF-␤-modified macrophages, a subset of activated macrophages, produce anti-inflammatory cytokines, suggesting that they may protect against inflammation-mediated injury. Here, macrophages modified ex vivo by IL-10/TGF-␤ (IL-10/TGF-␤ ⌴2) significantly attenuated renal inflammation, structural injury, and functional decline in murine adriamycin nephrosis (AN). These cells deactivated effector macrophages and inhibited CD4 ϩ T cell proliferation. IL-10/TGF-␤ ⌴2 expressed high levels of the regulatory co-stimulatory molecule B7-H4, induced regulatory T cells from CD4 cells in vitro,and increased the number of regulatory T cells in lymph nodes draining the kidneys in AN. The phenotype of IL-10/TGF-␤ ⌴2 did not switch to that of effector macrophages in the inflamed kidney, and these cells did not promote fibrosis. Taken together, these data demonstrate that IL-10/TGF-␤-modified macrophages effectively protect against renal injury in AN and may become part of a therapeutic strategy for chronic inflammatory disease.

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

“…Alternatively activated macrophage subsets induced by Th2 cytokines, immune complexes, or TGF-b/IL-10 treatment have proven efficacy in suppressing murine chemically induced colitis, experimental autoimmune encephalomyelitis, and kidney diseases (19)(20)(21)(22)(23). Our study shows that AvCystatin-Mregs acquire a phenotype characterized by the combined expression of markers assigned previously to the M2a and M2b subsets (34), reflecting the broad spectrum of macrophage activation as recently shown by Xue et al (37).…”

“…Cell-based therapies constitute a promising approach in which cells are differentiated into an immunosuppressive or regulatory phenotype and administered into patients. Experimentally, macrophages have been evaluated as good candidates for cell-based therapeutic intervention not only for atopic and autoimmune diseases, but also for the treatment of kidney diseases (18)(19)(20)(21)(22)(23)(24). Furthermore, regulatory macrophages have been successfully applied to human transplantation patients in first clinical trials to interfere with overt immune responses (25,26) and are discussed as a future therapy in solid-organ transplantation and beyond (27).…”

Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model

“…[13][14][15] In the context of kidney, IL-10 has been reported to effectively suppress the progression of acute and chronic renal damage in vivo. [16][17][18][19][20][21][22] However, the role of IL-10 in renal tubulointerstitial fibrosis has not been studied. Here, we used IL-10 À / À mice [23][24][25][26] with unilateral ureteral obstruction (UUO), a well-established model for kidney fibrosis, to investigate the roles of IL-10 in the progression of renal fibrosis.…”

Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation

“…Double and triple combinations of anti-inflammatory factors IL4, IL10 and TGFβ1 were previously shown to be more efficient than single cytokines, and induced robust tolerogenic phenotype in mouse and human macrophages [8,9,12]. In addition, macrophages stimulated by such cytokine combinations partially retained anti-inflammatory phenotype in vivo and their adoptive transfer protected mice from chronic inflammatory disorders including autoimmune type 1 diabetes and adriamycin nephrosis [8,9]. In our study, we have utilized triple combination of IL4, IL10 and TGFβ1…”

“…Thus, engineering a microenvironment around implanted devices or artificial tissues that would convert macrophages to a more pro-healing phenotype (generally designated as M2) is a promising approach to improve the integration of the device and attenuate the adverse immune reactions [6,7]. Furthermore, phenotype-controlled macrophages polarized by anti-inflammatory cytokines have previously been used to treat chronic inflammatory conditions and favored implant tolerance in mouse models [1,8,9].…”