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Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.

Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM, Thompson RW, Cheever AW, Urban JF, Wynn TA - PLoS Pathog. (2009)

Bottom Line: Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses.However, the role of Retnla in Th2-type immunity is unknown.The number of granuloma-associated eosinophils and serum IgE titers were also enhanced.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

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Retnla, Retnlb, and Retnlg expression is induced during Th2 inflammation.WT C57BL/6 (n = 5 per group) mice were sensitized i.p. with freshly isolated eggs of S. mansoni and challenged i.v. 14 days later. On day 7 after challenge mice were sacrificed and lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in several repeat experiments.
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ppat-1000393-g001: Retnla, Retnlb, and Retnlg expression is induced during Th2 inflammation.WT C57BL/6 (n = 5 per group) mice were sensitized i.p. with freshly isolated eggs of S. mansoni and challenged i.v. 14 days later. On day 7 after challenge mice were sacrificed and lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in several repeat experiments.

Mentions: To determine which members of the Relm gene family were most responsive to Th2 driven inflammation, 5000 viable S. mansoni eggs were injected intravenously into the lungs of C57BL/6 mice and expression of Retnla, Retnlb, Retn, and Retnlg mRNA was measured in the granulomatous tissues by quantitative real-time PCR. S. mansoni eggs have been shown in numerous studies to induce highly polarized Th2-dependent inflammatory responses by day 7 post-challenge [13],[34]. Development of the granulomatous response was associated with a significant increase in Retnla, Retnlb, and Retnlg mRNA (Fig. 1). However, Retnla was consistently upregulated to a much larger extent, often 100 times greater than Retnlb or Retnlg. In contrast, there was no increase of Retn (Resistin/FIZZ3) mRNA during the Th2-driven response. To elucidate the function of Retnla in the Th2 dependent inflammatory response, Retnla−/− mice were generated at Regeneron Pharmaceuticals using VelociGene technology [39],[40]. The genotypes of Retnla+/+, Retnla+/− and Retnla−/− offspring were determined by PCR analysis (data not shown). Retnla−/− mice were healthy and fertile and manifested no physical impairment. Naive Retnla−/− mice also showed no fundamental anomalies in the lymphoid compartment (Fig. S1). CD4+, CD8+ and CD4+D8+ populations were present at the expected frequencies and numbers in the thymus. B cells, CD4+ and CD8+ T cells, and natural killer cells were also present in wild-type proportions and numbers in the spleen.


Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.

Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM, Thompson RW, Cheever AW, Urban JF, Wynn TA - PLoS Pathog. (2009)

Retnla, Retnlb, and Retnlg expression is induced during Th2 inflammation.WT C57BL/6 (n = 5 per group) mice were sensitized i.p. with freshly isolated eggs of S. mansoni and challenged i.v. 14 days later. On day 7 after challenge mice were sacrificed and lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in several repeat experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663845&req=5

ppat-1000393-g001: Retnla, Retnlb, and Retnlg expression is induced during Th2 inflammation.WT C57BL/6 (n = 5 per group) mice were sensitized i.p. with freshly isolated eggs of S. mansoni and challenged i.v. 14 days later. On day 7 after challenge mice were sacrificed and lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in several repeat experiments.
Mentions: To determine which members of the Relm gene family were most responsive to Th2 driven inflammation, 5000 viable S. mansoni eggs were injected intravenously into the lungs of C57BL/6 mice and expression of Retnla, Retnlb, Retn, and Retnlg mRNA was measured in the granulomatous tissues by quantitative real-time PCR. S. mansoni eggs have been shown in numerous studies to induce highly polarized Th2-dependent inflammatory responses by day 7 post-challenge [13],[34]. Development of the granulomatous response was associated with a significant increase in Retnla, Retnlb, and Retnlg mRNA (Fig. 1). However, Retnla was consistently upregulated to a much larger extent, often 100 times greater than Retnlb or Retnlg. In contrast, there was no increase of Retn (Resistin/FIZZ3) mRNA during the Th2-driven response. To elucidate the function of Retnla in the Th2 dependent inflammatory response, Retnla−/− mice were generated at Regeneron Pharmaceuticals using VelociGene technology [39],[40]. The genotypes of Retnla+/+, Retnla+/− and Retnla−/− offspring were determined by PCR analysis (data not shown). Retnla−/− mice were healthy and fertile and manifested no physical impairment. Naive Retnla−/− mice also showed no fundamental anomalies in the lymphoid compartment (Fig. S1). CD4+, CD8+ and CD4+D8+ populations were present at the expected frequencies and numbers in the thymus. B cells, CD4+ and CD8+ T cells, and natural killer cells were also present in wild-type proportions and numbers in the spleen.

Bottom Line: Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses.However, the role of Retnla in Th2-type immunity is unknown.The number of granuloma-associated eosinophils and serum IgE titers were also enhanced.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

Show MeSH
Related in: MedlinePlus