An IL-1β-Dependent Switch in Innate Mucosal Immunity?

Innate Immunity Unit, Institut Pasteur, F-75724 Paris, France.
Immunity (Impact Factor: 21.56). 06/2010; 32(6):734-6. DOI: 10.1016/j.immuni.2010.06.012
Source: PubMed


Lymphoid tissues associated with mucosal surfaces harbor an elaborate immune defense system that plays a primary role in protection against invading pathogens. Developmentally related innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells, IL-22-producing cells expressing natural cytotoxicity receptors (NK22, NCR22, and NKR-LTi), and classical NK cells have been identified in mucosal-associated lymphoid tissues (MALT) in both man and mouse (Colonna, 2009). These diverse ILCs produce a variety of cytokines (IL-17, IL-22, and IFN-γ) that are implicated in protection against infection. In addition, these cytokines influence tissue remodeling after stress or inflammation and, when deregulated, can lead to serious disease, including autoimmunity and cancer exacerbation. Accordingly, it is essential to understand the mechanisms that control the generation of these innate lymphocytes and that regulate their function. Hughes et al. (2010) provide an important advance by demonstrating that the IL-1R1 can be used to identify human ILCs within secondary lymphoid tissue (SLT) that have strong IL-22-producing capacity. Moreover, they provide evidence suggesting that IL-1β, derived from dendritic cells (DCs), can modulate the fate of developing ILCs at mucosal sites, favoring the production of IL-22+ ILC while inhibiting generation of classical IFN-γ+ NK cells. These findings suggest a mechanistic solution for ILC diversification and, along with a recent report (Cella et al., 2010), demonstrate that regulation of IL-1β expression may fine-tune the functional activities of mucosal-associated ILCs under diverse conditions.

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    • "IL22 is a leukocyte-derived cytokine with key roles in intestinal defense and mucosal wound healing; some DBAþ mouse uNK cells transcribe and translate Il22 [11]. NCR1 is a stressactivated receptor found on NK cells and some T cell subsets [25] [26] that signals downstream via the transcription factor ETS1 [27]. Studies in mice with heterozygous loss of NCR1 function showed this receptor is essential in NK cell-mediated gastrointestinal mucosal immunity [26]. "
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    ABSTRACT: Activated uterine natural killer (uNK) cells are abundant in early human and mouse decidual basalis. In mice, distinct uNK cell subsets support early endothelial tip cell induction, the pruning of new vessels and initiation of spiral arterial modification. While genetic studies indicate that NK/uNK cell activation via receptors recognizing Class I MHC-derived peptides promotes human pregnancy, roles for other activation receptors expressed by NK cells, such as the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptors (NCR) are undefined in human or mouse pregnancies. Expression of AHR and NCR1 (ortholog of human NKp46) by gestation day (gd)10.5 mouse uNK cell subsets was measured by quantitative real-time RT-PCR. Early implantation sites from mice lacking expression of either receptor were examined histologically. Gd10.5 uNK cell subsets, separated by reactivity to Dolichos biflorus agglutinin lectin, differed in relative transcript abundance for Ahr and Ncr1. Quantitative histology revealed that, in comparison to C57BL/6 controls, implant sites from gd10.5 Ahr(-/-) and gd6.5-12.5 UkCa:B6.Ncr1(Gfp/Gfp) mice had normal uNK cell abundance but the uNK cells were smaller than normal and unable to trigger spiral arterial remodeling. Whole mount immunohistochemistry comparisons of viable, gd6.5-8.5 Ncr1(Gfp/Gfp) and C57BL/6 implant sites revealed deficits in implant site angiogenesis and conceptus growth in Ncr1(Gfp/Gfp). In mice, activation of AHR and of NCR1 by endogenous, as yet undefined ligands, contributes to uNK cell activation/maturation and angiogenic functions during early to mid-gestation pregnancy. MHC-independent activation of uNK cells also likely makes critical contributions to human pregnancy success.
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    ABSTRACT: The decidual reaction and the formation of new vessels in the uterus are two crucial processes during embryo implantation. Previously, we observed that lysophosphatidic acid (LPA) increases cyclooxygenase-2 derived - prostaglandin E2 production during implantation in the rat uterus and that it augments the expression of decidualization (IGFBP-1) and vascularization (IL-10) markers. Both cyclooxygenase and nitric oxide synthase (NOS) are known enzymes involved in these processes. Thus, we became interested in studying which factors contribute to LPA receptor-specific role during the decidual and the vascular reaction at implantation. We adopted a pharmacological approach in vitro incubating the uterus from rats on day 5 of gestation (day of implantation) with LPA, DGPP (a highly selective antagonist of LPA3, an LPA receptor) and cyclooxygenase and NOS selective and non-selective inhibitors. We determined NOS activity, prostaglandin E2 production and IGFBP-1 and IL-10 expression to evaluate decidualization and vascularization. We observed that LPA augmented the activity of the inducible NOS isoform through LPA1/LPA3. Inducible NOS activity participated in the induction of cyclooxygenase-2/prostaglandin E2 increase stimulated by LPA. Also, cyclooxygenase-2 derived prostaglandins mediated LPA-stimulatory action on NOS activity. Both cyclooxygenase-2 and inducible NOS mediated LPA effect on IGFBP-1 and IL-10 expression. These results suggest the participation of LPA/LPA3 in the production of crucial molecules involved in vascularization and decidualization, two main processes that prepare the uterine milieu for embryo invasion during implantation.
    Placenta 06/2013; 34(9). DOI:10.1016/j.placenta.2013.06.001 · 2.71 Impact Factor


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