IFN-γ-induced iNOS Expression in Mouse Regulatory Macrophages Prolongs Allograft Survival in Fully Immunocompetent Recipients

Abstract

Mouse monocytes exposed to macrophage colony-stimulating factor (M-CSF) and interferon-γ (IFN-γ) were driven to a novel suppressor phenotype. These regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarized macrophages and monocyte-derived dendritic cells (DCs). M regs completely suppressed polyclonal T cell proliferation through an inducible nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs eliminated cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5 × 10(6) donor-strain M regs before transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c (32.6 ± 4.5 versus 8.7 ± 0.2 days) and B6-to-BALB/c (31.1 ± 12 versus 9.7 ± 0.4 days) strain combinations. Nos2-deficient M regs did not prolong allograft survival, proving that M reg function in vivo is iNOS-dependent and mediated by living cells. M regs were detectable for at least 2 weeks postinfusion in allogeneic recipients. In their origin, development, phenotypic relationship with other in vitro-derived macrophages and functions, there are solid grounds to assert a near-equivalence of mouse and human M regs. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of suppressor macrophages. Clinical applications of M reg therapy as an adjunct immunosuppressive therapy are currently being investigated within The ONE Study.

Host antitumor resistance improved by the macrophage polarization in a chimera model of patients with HCC

“…12 The expression of both PD-1 and PD-L1 is induced in Mf by IFNg and/or TLR agonists, and binding of PD-1 with PD-L1 promotes M2 polarization, in particular M2a and M2cMf. 35 Similarly to PD-L1, certain microRNAs (e.g., miR-155 and miR-146a) are known to be induced in Mf upon activation with IFNg and/or TLR agonists. 36 These miRNAs repress SHIP in Mf and T cells, and consequently induce M2a/ M2c polarization.…”

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“…Regulatory macrophages express inducible nitric oxide synthase, MHC class II, and programmed death ligand 1, although little CD40 or CD86. 27 Regulatory macrophages are fundamentally distinct and do not express most markers found on M1 or M2 macrophages and have been shown to mitigate acute and chronic inflammation in different disease models. 28 Although regulatory macrophages modulate inflammatory immune responses, these cells do not actively participate in wound healing.…”

“…28 Although regulatory macrophages modulate inflammatory immune responses, these cells do not actively participate in wound healing. 27 Notably, peripheral blood monocytes have been divided into 2 subsets with distinct function and phenotype. The proinflammatory CD14+CD16+ subset exhibits high expression of proinflammatory cytokines, whereas the immunosuppressive monocytes are CD14+CD163+ and exhibit immunosuppressive mechanisms, including interleukin 10 (IL-10) production.…”

Laser Ablation–Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Detecting Rare Cells in Tissue Sections

“…In the current study, 50-nm gold particles were selected as a label because Mregs are known to be highly phagocytic (15). Optimal conditions for labeling were determined by incubating Mregs with gold particles at a range of concentrations for various periods prior to measuring cellular gold content by solution-based ICP-MS (Table I).…”

“…In addition, Mregs drive the development of activated induced regulatory T cells that, in turn, suppress the proliferation of effector T cells and inhibit the maturation of monocyte-derived dendritic cells in response to TNF-a (14). Therefore, it is thought that when Mregs are administered to an allogeneic recipient they can initiate a feedforward loop of immunological regulation, potentially leading to the long-term acceptance of a foreign transplant (15).…”