Wang Y, Chang J, Yao B, et al. in allograft injury and a promising target to improve transplant outcomes. INTRODUCTION Recent advances in basic science have placed macrophages at the forefront of research for the fields of immunology and transplantation. Historically, macrophages were viewed primarily as scavenger cells whose primary function was the clearance of pathogens, dead cells, and foreign molecules; however, there is renewed interest in macrophages due to increasing evidence of their important role in tissue inflammation Aniracetam and repair. Remarkable advances in the understanding of macrophage development and function demonstrate key roles for macrophages in organogenesis, tissue homeostasis, and promotion of tissue injury. Consequently, macrophages represent a promising therapeutic target for clinical transplantation. Macrophages are key effector cells of the innate immune system. While the role of adaptive immunity, which is comprised of cellular (T cell) and humoral (B cell) immunity, is well recognized in allograft rejection Aniracetam and tolerance, the importance of innate immunity is less well-appreciated despite the fact that innate immune cells make up 38C60% of allograft infiltrating cells.1 In this review, macrophage phenotypes, macrophage contributions to allograft injury, and macrophages as a therapeutic target in solid organ transplants will be discussed with an emphasis on kidney transplantation. MACROPHAGES Macrophages are tissue resident cells that possess a diverse repertoire of surface receptors, including pattern recognition receptors for damage associated molecular patterns (DAMPs), complement products, chemokines, Fc fragments, Toll-like receptors (TLRs), cell debris, and necrotic cells.2C4 Macrophages are also able to express major histocompatibility complex (MHC) class II on their surface, which allows macrophages to play a role in antigen presentation. These features permit macrophages to respond to various etiologies of tissue injury, whether immunologic (including complement activation, T cell activation, and antibody production), nonimmune (ischemic, mechanical, chemical), or infectious.5 Activation Aniracetam of macrophage surface receptors results in phagocytosis and production of cytokines, reactive oxygen species, and reactive nitrogen species. Thus, responses that promote complement activation, antibody production, and cell injury or death will dramatically affect the activation state and effector functions of macrophages. One unique feature of macrophages within the allograft is that donor macrophages are transferred along with the donor organ at time of transplant and subsequently recipient monocyte-derived macrophages are recruited to the allograft.6 Historical perspective on profiling of macrophage phenotypes Work done in the 1980s described Aniracetam how IFN produced by T helper type 1 (Th1) cells could activate macrophages.7 As this was the first description of macrophage activation, these macrophages came to be labeled as classically activated. In the 1990s, additional mediators of macrophage activation were identified, namely the Th2 cytokines, IL-4 and IL-13. Activation by IL-4/IL-13 led to the generation of a phenotypically different macrophage compared to the classically activated macrophage.8 Thus, the macrophages activated by IL-4/IL-13 were termed alternatively activated. In 2000, studies of activated macrophages from the Th1 (BL/6) mouse strain compared to the Th2 (BALB/c) mouse strain were found to have differing metabolic profiles of arginine.9 Based on these studies and in an effort to emulate the nomenclature of the Th1 and Th2 system, the M1/M2 paradigm for macrophage nomenclature was proposed.9 In this classification system, M1 macrophages represented the classically activated macrophages and alternatively activated macrophages were designated as M2. However, as work continued to further examine macrophage activation over the next decade, it became apparent that many alternative activators of macrophages Aniracetam existed and produced a variety of macrophage phenotypes. M1 polarized macrophages M1 macrophages are polarized towards proinflammatory functions (Figure 1). Historically, M1 macrophages were labeled as classically activated due to the finding that they were stimulated by IFN or LPS under conditions. Polarization towards M1 macrophages involves activation of signaling pathways and regulation of transcriptional and posttranscriptional events. Rabbit Polyclonal to EGFR (phospho-Ser1071) Activation of STAT, NF-?B, and interferon-regulatory factor (IRF) signaling pathways produces M1 polarization. When macrophages are stimulated by IFN, JAK-mediated tyrosine phosphorylation is triggered, leading to STAT signaling. STAT1 translocates to the nucleus to direct transcription of mediators such as inducible nitric oxide synthase (iNOS), MHC class II, and IL-12. Binding of Toll-like receptors on the macrophage surface by microbial products or DAMPs triggers activation of the transcription factor NF-?B, which promotes expression of several inflammatory mediators, including IL-1, IL-6, TNF, and COX2.10 In addition, signaling through IRF 3 and IRF 5 activates transcription of genes encoding subunits for production of IL-12 and IL-23, and also represses the gene encoding IL-10.11,12 Thus, M1 polarized macrophages express high levels of MHC class II, produce proinflammatory cytokines, iNOS, and release reactive oxygen and nitrogen species. Open in a separate window Figure 1. Macrophage polarization exists along a continuum. At one end of the spectrum is the proinflammatory M1 phenotype, or M(IFN) macrophages. M1 macrophages are.