Invariant natural killer T (iNKT) cells are an important source of both T helper type 1 (Th1) and Th2 cytokines, through which they can exert beneficial, as well as deleterious, effects in a variety of inflammatory diseases. This functional heterogeneity raises the question of how far phenotypically distinct subpopulations are responsible for such contrasting activities. In this study, we identify a particular set of iNKT cells that lack the NK1.1 marker (NK1.1neg) and secrete high amounts of interleukin (IL)-17 and low levels of interferon (IFN)-γ and IL-4. NK1.1neg iNKT cells produce IL-17 upon synthetic (α-galactosylceramide [α-GalCer] or PBS-57), as well as natural (lipopolysaccharides or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi), ligand stimulation. NK1.1neg iNKT cells are more frequent in the lung, which is consistent with a role in the natural immunity to inhaled antigens. Indeed, airway neutrophilia induced by α-GalCer or lipopolysaccharide instillation was significantly reduced in iNKT-cell–deficient Jα18−/− mice, which produced significantly less IL-17 in their bronchoalveolar lavage fluid than wild-type controls. Furthermore, airway neutrophilia was abolished by a single treatment with neutralizing monoclonal antibody against IL-17 before α-GalCer administration. Collectively, our findings reveal that NK1.1neg iNKT lymphocytes represent a new population of IL-17–producing cells that can contribute to neutrophil recruitment through preferential IL-17 secretion.

Invariant natural killer T (iNKT) cells constitute a subpopulation of T cells that recognize glycolipids presented bythymic precursors ͉ ␣-GalCer ͉ CD1d ͉ cytokines

Asthma results from an intrapulmonary allergen-driven Th2 response and is characterized by intermittent airway obstruction, airway hyperreactivity, and airway inflammation. An inverse association between allergic asthma and microbial infections has been observed. Microbial infections could prevent allergic responses by inducing the secretion of the type 1 cytokines, IL-12 and IFN-γ. In this study, we examined whether administration of bacterial LPS, a prototypic bacterial product that activates innate immune cells via the Toll-like receptor 4 (TLR4) could suppress early and late allergic responses in a murine model of asthma. We report that LPS administration suppresses the IgE-mediated and mast cell-dependent passive cutaneous anaphylaxis, pulmonary inflammation, airway eosinophilia, mucus production, and airway hyperactivity. The suppression of asthma-like responses was not due to Th1 shift as it persisted in IL-12−/− or IFN-γ−/− mice. However, the suppressive effect of LPS was not observed in TLR4- or NO synthase 2-deficient mice. Our findings demonstrate, for the first time, that LPS suppresses Th2 responses in vivo via the TLR4-dependent pathway that triggers NO synthase 2 activity.

Beta2-adrenergic receptor (B2AR) signaling is known to impairKeywords: Foxp3 · Noradrenaline · Sympathetic nervous system · Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionLymphoid organs such as the spleen and the lymph nodes are richly innervated by the sympathetic nervous system (SNS), especially within T-cell areas [1]. Immune responses can be moduCorrespondence: Dr. Alexandre S. Basso e-mail: asbasso@unifesp.br lated by catecholamines released upon sympathetic activity only if immune cells are able to respond to them by expressing functional catecholaminergic receptors. Indeed, the beta2-adrenergic receptor (B2AR) has been described as the main adrenergic receptor expressed in immune cells, including dendritic cells, macrophages, CD4 + T cells, CD8 + T cells, and B cells [2,3]. Furthermore, increased noradrenaline release in the spleen followed by the activation of antigen-specific T and B cells has been already reported, indicating that an adaptive immune response can lead to enhanced SNS activity within lymphoid organs [4]. Taken 1002 Marcia. G. Guereschi et al. Eur. J. Immunol. 2013. 43: 1001-1012 sympathetic innervation of lymphoid organs, SNS activation due to adaptive immune responses, and the expression of adrenergic receptors by immune cells build a solid case supporting the concept that the SNS represents a feedback mechanism that is able to modulate immune responses [5]. Thus far, it has been shown that B2AR is expressed in CD4 + naïve T cells and Th1 clones while it is completely absent in Th2 clones [3,6]. CD4 + T-cell stimulation along with B2AR activation decreased IL-2 production and IL-2 receptor α-chain (CD25) expression in a cAMP-dependent way [3,[6][7][8]. Activation of Th1 clones in the presence of a B2AR agonist may also impair IL-2 and IFN-γ expression [6,7]. Furthermore, by selective inhibition of IL-12 production in LPS-stimulated human dendritic cells, B2AR agonists were found to block in vitro differentiation of neonatal CD4 + T cells into IFN-γ-producing cells, favoring IL-4 production instead [9]. Therefore information on SNS-mediated modulation of CD4 + T-cell immune responses via B2AR activation has been concentrated on the dichotomy Th1/Th2; and in general these data point to a role for B2AR activation in inhibiting the development of Th1 responses [6,8,9]. Very little is known on how adrenergic neurotransmitters could modulate the activity of other CD4 + T-cell subsets, among them Foxp3− T cells possess transcripts for the beta1-adrenergic receptor (B1AR) and the alpha2A-adrenergic receptor (A2aAR), besides the B2AR (Supporting Information Fig. 1A). Among those three, the B2AR is far more expressed than the other two (Supporting Information Fig. 1A). that Treg cells also express the B2AR, the B1AR, and the A2aAR (Supporting Information Fig. 1B). In Treg cells, B2AR was also expressed at higher levels as compared to B1AR and A2aAR (Supporting Information Fig. 1B). When comparing B2AR mRN...

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BackgroundThe tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed.AimWe explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease.MethodsSprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed.ResultsPre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-β protein production was significantly lower in Hemin-treated animals.ConclusionTreatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.

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Invariant natural killer T (iNKT) cells represent a particular subset of T lymphocytes capable of producing several cytokines, which exert regulatory or effector functions, following stimulation of the T cell receptor. In this study, we investigated the influence of iNKT cells on the development of experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). After injection of anti-GBM serum, the number of kidney iNKT cells rapidly increased. iNKT cell-deficient mice (Jalpha18-/-) injected with anti-GBM serum demonstrated worse renal function, increased proteinuria, and greater glomerular and tubular injury compared with similarly treated wild-type mice. We did not detect significant differences in Th1/Th2 polarization in renal tissue that might have explained the severity of disease in Jalpha18-/- mice. Interestingly, expression of both TGF-beta and TGF-beta-induced (TGFBI) mRNA was higher in wild-type kidneys compared with Jalpha18-/- kidneys, suggesting a possible protective role for TGF-beta in anti-GBM GN. Administration of an anti-TGF-beta neutralizing antibody significantly enhanced the severity of disease in wild-type, but not Jalpha18-/-, mice. In conclusion, in experimental anti-GBM GN, iNKT cells attenuate disease severity and TGF-beta has a renoprotective role.