L-arginine metabolism in myeloid cells controls T-lymphocyte functions

Bronte, Vincenzo; Serafini, Paolo; Mazzoni, Alessandra; Segal, David M.; Zanovello, Paola

doi:10.1016/s1471-4906(03)00132-7

Cited by 528 publications

(438 citation statements)

References 40 publications

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“…Consistent with our observations, they have found very little arginase I activity in Gr-1 ϩ CD11b ϩ cells, whereas the bulk of activity was associated with Gr-1 Ϫ CD11b ϩ macrophages (38). Bronte and colleagues (20,30) have recently demonstrated that induction of arginase and iNOS together causes activated T lymphocytes to undergo apoptosis. In this study, we for the first time demonstrated that this process of simultaneous activation of iNOS and arginase I indeed takes place in TAM.…”

Section: Figuresupporting

confidence: 89%

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Kusmartsev

Gabrilovich

2005

The Journal of Immunology

388

325

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It is well established that tumor progression is associated with the accumulation of myeloid suppressive cells, which in mice include Gr-1+ immature myeloid cells and F4/80+ macrophages. The paradox is that with the exception of terminal stages of the disease or chemotherapy treatment, tumor-bearing mice or cancer patients do not display a profound systemic immune suppression. We therefore raised the question as to whether myeloid cell-mediated T cell suppression is controlled at a local level at the site of the tumor. We have demonstrated that after adoptive transfer to tumor-bearing recipients, Gr-1+ (immature myeloid cells) freshly isolated from spleens of tumor-bearing mice become F4/80+ tumor-associated macrophages (TAM). These TAM, but not F4/80+ macrophages or Gr-1+ cells freshly isolated from spleens of tumor-bearing or naive mice were able to inhibit T cell-mediated immune response in vitro via induction of T cell apoptosis. Arginase and NO were both responsible for the apoptotic mechanism, and were seen only in TAM, but not in freshly isolated Gr1+ cells. Using the analysis of STAT activity in combination with STAT knockout mice, we have determined that STAT1, but not STAT3 or STAT6, was responsible for TAM-suppressive activity.

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Section: Figuresupporting

confidence: 89%

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Kusmartsev

Gabrilovich

2005

The Journal of Immunology

388

325

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“…A hallmark feature of the M2 population is that they express F4/80, CD301, IL-10, and arginase 1 (37,38), the latter of which has been shown to inhibit NOS (iNOS) activity (41). Such a combination of factors may help to preserve normal adipocyte function by promoting tissue repair and angiogenesis in the increasing AT mass (42).…”

Section: Macrophages Major Constituents Of At and Mediators Of Remodmentioning

confidence: 99%

Adipose tissue remodeling and obesity

Sun¹,

Kusminski²,

Scherer³

2011

J. Clin. Invest.

1,552

1,381

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To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth. IntroductionAdipose tissue (AT) can respond rapidly and dynamically to alterations in nutrient deprivation and excess through adipocyte hypertrophy and hyperplasia, thereby fulfilling its major role in wholebody energy homeostasis. AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and thus, features such as reduced angiogenic remodeling, ECM overproduction, a heightened state of immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads (1). However, not all AT expansion is necessarily associated with pathological changes. The concept of the "metabolically healthy obese" state (2) suggests that some individuals can preserve systemic insulin sensitivity on the basis of "healthy" AT expansion, bypassing all of the aforementioned pathological consequences associated with obesity (3), thereby also avoiding the obesity-associated lipotoxic side effects. Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate. A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages; moreover, merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4). AT is therefore an ideal model system to study rapid alterations in tissue expansion and reduction, as it adapts to a differential nutrient supply. Here, we will focus on key aspects of the intricate dynamics of AT remodeling and subsequent inflammatory consequences that arise from obesity.

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“…The expression of Arg-1 and/or iNOS by macrophages and DCs is well recognized to have immunosuppressive consequences (29,(35)(36)(37), however, tolerogenic DCs can also dampen the magnitude of T cell activation through mechanisms beyond Arg-1 and iNOS. We found that expression of IL-12p40, an important contributor to the development of Th1 cells (38,39), was reduced in RA-DCs (data not shown).…”

Section: Discussionmentioning

confidence: 99%

All-Trans Retinoic Acid Induces Arg-1 and iNOS Producing Dendritic Cells With T Cell Inhibitory Function.

Bhatt¹,

Qin²,

Bennett³

et al. 2014

Transplantation

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Hepatic stellate cells (HSC) are a major source of the immunoregulatory metabolite all-trans retinoic acid (ATRA), which may contribute to the generation of tolerogenic dendritic cells (DCs) in the liver. The present study seeks to clarify the mechanism(s) through which ATRA promotes the development of tolerogenic DCs. Though bone marrow-derived ATRA-treated DCs (RA-DCs) and conventional DCs had comparable surface phenotype, RA-DCs had diminished stimulatory capacity and could directly inhibit the expansion of DC/OVA-stimulated OT-II T cells. Arginase I (Arg-1) was found promote suppression because: a) ATRA was a potent inducer of Arg-1 protein and activity, b) the Arg-1 inhibitor nor-NOHA partially reversed suppression, and c) the suppressive function of RA-DCs was partially compromised using OT-II T cells from GCN2 −/− mice, which are insensitive to Arg-1. Inducible nitric oxide synthase (iNOS), however, was found to be a more significant contributor to RA-DC function because: a) ATRA potentiated the expression of IFN-γ induced iNOS, b) suppressive function in RA-DCs was blocked by the iNOS inhibitor L-NMMA, and c) RA-DCs derived from iNOS −/− mice exhibited near complete loss of tolerogenic function, despite sustained Arg-1 activity. The expression of iNOS and the suppressive function of RA-DCs were dependent on both IFN-γ and ATRA. Furthermore, the in vivo behavior of RA-DCs proved to be consistent with their in vitro behavior. Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-γ treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance.

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L-arginine metabolism in myeloid cells controls T-lymphocyte functions

Cited by 528 publications

References 40 publications

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Adipose tissue remodeling and obesity

All-Trans Retinoic Acid Induces Arg-1 and iNOS Producing Dendritic Cells With T Cell Inhibitory Function.

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