Genetics of SLE: Functional Relevance for Monocytes/Macrophages in Disease

Byrne, J.; Gabhann, Joan Ní; Lazzari, Elisa; Mahony, Rebecca; Smith, Siobhan; Stacey, Kevin; Wynne, Claire; Jefferies, Caroline A.

doi:10.1155/2012/582352

Cited by 48 publications

(37 citation statements)

References 158 publications

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“…A percentage of SLE patients exhibits a loss in Trex1 function (8). In addition, we have shown that both TLR7 and TLR9 (19), which have been associated with the development of SLE, upregulate Trex1, and that, in its absence, responses to these TLR ligands result in an augmented inflammatory response.…”

Section: Discussionmentioning

confidence: 79%

“…In SLE and other autoimmune diseases, a plethora of immune cells are dysfunctional, including T and B cells, which together result in high levels of circulating autoreactive Abs (18). Macrophages from SLE patients are more active, with increased cytokine production and an increase in the ability to present self-Ags to T cells, together with a decreased ability to perform apoptotic clearance (19).…”

mentioning

confidence: 99%

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The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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The three-prime repair exonuclease 1 (TREX1) is the most abundant exonuclease in mammalian cells. Mutations in Trex1 gene are being linked to the development of Aicardi–Goutières syndrome, an inflammatory disease of the brain, and systemic lupus erythematosus. In clinical cases and in a Trex1-deficient murine model, chronic production of type I IFN plays a pathogenic role. In this study, we demonstrate that Trex1−/− mice present inflammatory signatures in many different organs, including the brain. Trex1 is highly induced in macrophages in response to proinflammatory stimuli, including TLR7 and TLR9 ligands. Our findings show that, in the absence of Trex1, macrophages displayed an exacerbate proinflammatory response. More specifically, following proinflammatory stimulation, Trex1−/− macrophages exhibited an increased TNF-α and IFN-α production, higher levels of CD86, and increased Ag presentation to CD4+ T cells, as well as an impaired apoptotic T cell clearance. These results evidence an unrevealed function of the Trex1 as a negative regulator of macrophage inflammatory activation and demonstrate that macrophages play a major role in diseases associated with Trex1 mutations, which contributes to the understanding of inflammatory signature in these diseases.

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

Pereira-Lopes

Celhar

Sans-Fons

et al. 2013

The Journal of Immunology

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“…Since aberrant T cells polarization, altered HO-1 expression (32–34) and/or monocyte activity (35–37) have been reported in various inflammatory diseases, it raises the possibility that the CD16+monocyte HO-1-T cell polarization axis may also play a pivotal role in the etiology and prognosis of such inflammatory diseases. HO-1 activity and levels can be regulated by multiple factors, (9) and therefore understanding the mechanisms of HO-1 mediated T cell polarization may not only provide insight into the etiology of diseases and but also may offer potential therapy targets for such diseases.…”

Section: Discussionmentioning

confidence: 99%

Hemin Controls T Cell Polarization in Sickle Cell Alloimmunization

Zhong

Bao

Friedman

et al. 2014

The Journal of Immunology

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Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused red blood cells (RBCs) with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and T helper (Th) responses with higher circulating Th1 (IFN-γ+) cytokines in chronically transfused SCD patients with alloantibodies as compared to those without alloantibodies. Since monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to RBC breakdown product, hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T-cell-monocyte cocultures from healthy volunteers through monocyte anti-inflammatory heme degrading enzyme HO-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of HO-1. Furthermore, IL-12, which contributed to a pro-inflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conductive to alloimmunization.

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“…studies have identified a number of genes that are linked to IFN production or signaling, such as IRF5, TYK2, IFIH1, and TLR7 (16,17). Type I IFNs have also recently been found to be central to inflammatory responses in the lung in response to viral or environmental challenges.…”

Section: Introductionmentioning

confidence: 99%