Interleukin-15-Dependent NKp46+ Innate Lymphoid Cells Control Intestinal Inflammation by Recruiting Inflammatory Monocytes

Schulthess, Julie; Meresse, Bertrand; Ramiro-Puig, Emma; Montcuquet, Nicolas; Darche, Sylvie; Bègue, Bernadette; Ruemmele, F.; Combadière, Christophe; Santo, James P. Di; Buzoni‐Gatel, Dominique; Cerf‐Bensussan, Nadine

doi:10.1016/j.immuni.2012.05.013

Cited by 102 publications

(90 citation statements)

References 53 publications

(68 reference statements)

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“…Synergistic expression of ROP16 and GRA15 increases parasite susceptibility within IFN-␥-and TNF-␣-stimulated macrophages. Inflammatory macrophages that are recruited to the intestine are critically important for the host to limit Toxoplasma replication and promote host resistance at the site of infection (32,33). Since ROP16 and GRA15 had a drastic effect on parasite burden in vivo, we tested whether the type II engineered strains differed in their ability to evade macrophage toxoplasmacidal mechanisms elicited by stimulation with IFN-␥ and TNF-␣, cytokines that are expressed in the intestine following oral infection (20).…”

Section: Figmentioning

confidence: 99%

“…TFBS enrichment analysis (DiRE) was performed on all Peyer's patch genes that were upregulated, on average, 1.7-fold following infection compared to the level of regulation in the uninfected sample [0.8 Ͻ log 2 (average gene expression of type II and estingly, Ccl1 and Ccl3 chemokine gene expression was highly induced by the IIϩROP16 I strain, while coagulation factors (F5 and F13a1) were downregulated. CCL3 and its receptor, CCR1, were recently shown to be required for inflammatory monocyte recruitment to the intestine of Toxoplasma-infected mice, which in turn limited the intestinal parasite burden (32). Considering that a putative STAT5 TFBS sequence is 500 bp upstream of the transcriptional start site of CCL3 (not shown), it remains to be determined whether gene expression of Ccl3 by the IIϩROP16 I strain requires host STAT5 and/or NF-B.…”

Section: Figmentioning

confidence: 99%

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Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15

et al. 2013

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c Toxoplasma gondii transmission between intermediate hosts is dependent on the ingestion of walled cysts formed during the chronic phase of infection. Immediately following consumption, the parasite must ensure survival of the host by preventing adverse inflammatory responses and/or by limiting its own replication. Since the Toxoplasma secreted effectors rhoptry 16 kinase (ROP16) and dense granule 15 (GRA15) activate the JAK-STAT3/6 and NF-B signaling pathways, respectively, we explored whether a particular combination of these effectors impacted intestinal inflammation and parasite survival in vivo. Here we report that expression of the STAT-activating version of ROP16 in the type II strain (strain II؉ROP16 I ) promotes host resistance to oral infection only in the context of endogenous GRA15 expression. Protection was characterized by a lower intestinal parasite burden and dampened inflammation. Host resistance to the II؉ROP16 I strain occurred independently of STAT6 and the T cell coinhibitory receptors B7-DC and B7-H1, two receptors that are upregulated by ROP16. In addition, coexpression of ROP16 and GRA15 enhanced parasite susceptibility within tumor necrosis factor alpha/gamma interferon-stimulated macrophages in a STAT3/6-independent manner. Transcriptional profiling of infected STAT3-and STAT6-deficient macrophages and parasitized Peyer's patches from mice orally challenged with strain II؉ROP16 I suggested that ROP16 activated STAT5 to modulate host gene expression. Consistent with this supposition, the ROP16 kinase induced the sustained phosphorylation and nuclear localization of STAT5 in Toxoplasma-infected cells. In summary, only the combined expression of both GRA15 and ROP16 promoted host resistance to acute oral infection, and Toxoplasma may possibly target the STAT5 signaling pathway to generate protective immunity in the gut.

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15

et al. 2013

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“…We have recently shown that, in the acute stage of infection, DCs secrete high levels of IL-12, triggering adaptive immunity (9). The proinflammatory cytokine IFN-g produced mainly by activated innate lymphoid cells, NK, and T cells is the major driving factor for host protection against this intracellular pathogen (10,11). In our previous studies, we detected that Ly6C high Gr1 + monocytes were crucial during the acute stage of T. gondii infection, producing high amounts of TNF, inducible NO synthase (iNOS), and reactive oxygen intermediates (ROS), which directly contributed to the control of the parasite burden in the host (6,7,12,13).…”

mentioning

confidence: 99%

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Biswas

Bruder

Wolf

et al. 2015

The Journal of Immunology

100

125

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Cerebral infection with the parasite Toxoplasma gondii is followed by activation of resident cells and recruitment of immune cells from the periphery to the CNS. In this study, we show that a subset of myeloid cells, namely Ly6ChighCCR2+ inflammatory monocytes that infiltrate the brain upon chronic T. gondii infection, plays a decisive role in host defense. Depletion of this monocyte subset resulted in elevated parasite load and decreased survival of infected mice, suggesting their crucial role. Notably, Ly6ChighCCR2+ monocytes governed parasite control due to production of proinflammatory mediators, such as IL-1α, IL-1β, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6ChighCCR2+ monocytes were also able to produce the regulatory cytokine IL-10, revealing their dual feature. Moreover, we confirmed by adoptive transfer that the recruited monocytes further develop into two distinct subpopulations contributing to parasite control and profound host defense. The differentiated Ly6CintCCR2+F4/80int subset upregulated MHC I and MHC II molecules, suggesting dendritic cell properties such as interaction with T cells, whereas the Ly6CnegF4/80high cell subset displayed elevated phagocytic capacity while upregulating triggering receptor expressed on myeloid cells-2. Finally, we have shown that the recruitment of Ly6Chigh monocytes to the CNS is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6Chigh monocytes upon cerebral toxoplasmosis and reveal the behavior of further differentiated myeloid-derived mononuclear cell subsets in parasite control and immune regulation of the CNS.

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“…Dans l'intestin, les ILC1 sont la source innée prédominante d'IFN- en réponse à l'IL-12 ou, par exemple, à une infection intestinale par le parasite Toxoplasma gondii [25]. Elles participent en effet, avec les lymphocytes T qui produisent de l'IFN-, au contrôle de la réplication du parasite et assurent le recrutement des monocytes inflammatoires [25,34]. Les souris Rag1 -/-Tbet -/-comme les souris Rag1 -/-Ifng -/-sont aussi plus sensibles à l'infection par Clostridium difficile que les souris uniquement invalidées pour le gène Rag1.…”

Section: Les Ilc1unclassified