ABSTRACT
The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2-/- mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2-/- BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-ß1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.
Subject(s)
Apoptosis , Macrophages , Membrane Glycoproteins , Mice, Inbred C57BL , Receptors, Immunologic , STAT Transcription Factors , Signal Transduction , Animals , Macrophages/metabolism , Receptors, Immunologic/metabolism , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , STAT Transcription Factors/metabolism , Janus Kinases/metabolism , Kidney/pathology , Kidney/metabolism , Mice, Knockout , Male , Fibrosis , Reperfusion Injury/pathology , Reperfusion Injury/metabolism , Reperfusion Injury/genetics , Ureteral Obstruction/pathology , Ureteral Obstruction/metabolism , Ureteral Obstruction/complications , Cell Polarity , TOR Serine-Threonine Kinases/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/geneticsABSTRACT
ABSTRACT: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.
Subject(s)
Biomarkers , Kidney Diseases , Triggering Receptor Expressed on Myeloid Cells-1 , Humans , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Kidney Diseases/metabolism , Biomarkers/metabolism , Receptors, Immunologic/metabolism , Membrane Glycoproteins/metabolism , Diabetic Nephropathies/metabolism , Signal Transduction , Acute Kidney Injury/metabolism , Animals , Carcinoma, Renal Cell/metabolismABSTRACT
Organ transplantation requires the use of immunosuppressive medications that lack antigen specificity, have many adverse side effects, and fail to induce immunological tolerance to the graft. The safe induction of tolerance to allogeneic tissue without compromising host responses to infection or enhancing the risk of malignant disease is a major goal in transplantation. One promising approach to achieve this goal is based on the concept of "negative vaccination." Vaccination (or actively acquired immunity) involves the presentation of both a foreign antigen and immunostimulatory adjuvant to the immune system to induce antigen-specific immunity. By contrast, negative vaccination, in the context of transplantation, involves the delivery of donor antigen before or after transplantation, together with a "negative adjuvant" to selectively inhibit the alloimmune response. This review will explore established and emerging negative vaccination strategies for promotion of organ or pancreatic islet transplant tolerance. These include donor regulatory myeloid cell infusion, which has progressed to early-phase clinical trials, apoptotic donor cell infusion that has advanced to nonhuman primate models, and novel nanoparticle antigen-delivery systems.