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Cited by 213Parasites and Host InteractionsIL-33, ST2, and ILC PathwaysParasitic Diseases Research and Treatment

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Retnla (Relmα/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity

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Pesce, John T., Ramalingam, Thirumalai R., Wilson, Mark S., Mentink-Kane, Margaret M., Thompson, Robert W., Cheever, Allen W., Urban, Joseph F., Wynn, Thomas A.·2009·PLoS Pathogens
DOI 10.1371/journal.ppat.1000393PMC PMC2663845
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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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Figure 1 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.
Figure 1 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.CC0 · PubMed Central
Figure 2 Retnla is localized to the lung parenchyma surrounding the granulomas. (A) Lung samples from naïve, (B) S. mansoni i.v. egg challenged (primary) and (C) i.p. egg sensitized and challenged (secondary) Retnla−/− mice were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×20. Small inset in panel C magnification ×10.
Figure 2 Retnla is localized to the lung parenchyma surrounding the granulomas. (A) Lung samples from naïve, (B) S. mansoni i.v. egg challenged (primary) and (C) i.p. egg sensitized and challenged (secondary) Retnla−/− mice were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×20. Small inset in panel C magnification ×10.CC0 · PubMed Central
Figure 3 Pulmonary granuloma formation is increased in the absence of Retnla. Naïve, S. mansoni i.v. egg challenged (primary) and i.p. egg sensitized and challenged (secondary) WT and Retnla−/− mice were sacrificed on day 7 post i.v. egg-challenge. Right lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Primary WT (n = 9), Primary Retnla−/− (n = 8), Secondary WT (n = 9), Secondary Retnla−/− (n = 10). Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT (A). The left lobes from each mouse were examined histologically to evaluate the size of granulomas as a measure of inflammation (B) and the percentage of granuloma-associated eosinophils (C). Serum was also collected to quantify SEA-specific IgE (mean ng/ml±SEM) (D). Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in two repeat experiments.
Figure 3 Pulmonary granuloma formation is increased in the absence of Retnla. Naïve, S. mansoni i.v. egg challenged (primary) and i.p. egg sensitized and challenged (secondary) WT and Retnla−/− mice were sacrificed on day 7 post i.v. egg-challenge. Right lung RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg. Primary WT (n = 9), Primary Retnla−/− (n = 8), Secondary WT (n = 9), Secondary Retnla−/− (n = 10). Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT (A). The left lobes from each mouse were examined histologically to evaluate the size of granulomas as a measure of inflammation (B) and the percentage of granuloma-associated eosinophils (C). Serum was also collected to quantify SEA-specific IgE (mean ng/ml±SEM) (D). Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in two repeat experiments.CC0 · PubMed Central
Figure 4 Retnla is localized to granuloma-associated eosinophils in the liver. Control WT C57BL/6 mice (n = 5) were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 and 12 post infection and liver RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg (A). Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Livers from naïve Retnla−/− mice (B) and Retnla−/− mice infected with 30–35 cercariae for 9 (C) and 12 wk (D) were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×10 (B, C) and ×20 (D). (E) WT C57BL/6 mice were infected with 35 S. mansoni cercariae and on week 9, eosinophils were purified from perfused livers by positive selection using the Siglec-F antibody. The granuloma-associated leukocytes were separated into nonfractionated, Siglec-F− (eosinophil-negative), and Siglec-F+ (eosinophil-positive) fraction, mRNA was isolated, and then analyzed by real-time PCR analysis for Retnla. The data shown are means±SEM (n = 5/group). (F) WT C57BL/6 mice and IL-5−/− mice were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 (WT n = 9, IL-5−/− n = 10) and 12 (WT n = 6, IL-5−/− n = 8) post infection and liver RNA specimens were prepared individually for real-time PCR analysis of Retnla. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in two repeat experiments.
Figure 4 Retnla is localized to granuloma-associated eosinophils in the liver. Control WT C57BL/6 mice (n = 5) were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 and 12 post infection and liver RNA specimens were prepared individually for real-time PCR analysis of Retnla, Retnlb, Retn, and Retnlg (A). Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Livers from naïve Retnla−/− mice (B) and Retnla−/− mice infected with 30–35 cercariae for 9 (C) and 12 wk (D) were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×10 (B, C) and ×20 (D). (E) WT C57BL/6 mice were infected with 35 S. mansoni cercariae and on week 9, eosinophils were purified from perfused livers by positive selection using the Siglec-F antibody. The granuloma-associated leukocytes were separated into nonfractionated, Siglec-F− (eosinophil-negative), and Siglec-F+ (eosinophil-positive) fraction, mRNA was isolated, and then analyzed by real-time PCR analysis for Retnla. The data shown are means±SEM (n = 5/group). (F) WT C57BL/6 mice and IL-5−/− mice were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 (WT n = 9, IL-5−/− n = 10) and 12 (WT n = 6, IL-5−/− n = 8) post infection and liver RNA specimens were prepared individually for real-time PCR analysis of Retnla. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Similar results were obtained in two repeat experiments.CC0 · PubMed Central
Figure 5 Inflammation and fibrosis are exacerbated in S. mansoni infected Retnla−/− mice. (A) Control WT C57BL/6 mice (N = 19 wk 9, N = 7 wk 12) and Retnla−/− (N = 17 wk 9, N = 8 wk 12) mice were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 and 12 post infection and liver RNA specimens were prepared individually for real-time RT-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. In separate studies, the livers of S. mansoni infected mice were analyzed on wk 9 (WT N = 19, KO N = 17), 12 (WT N = 7, KO N = 8), and 25 (WT N = 10, KO N = 8) to evaluate the size of granulomas (Mean granuloma volume±SEM) as a measure of inflammation (B) and hydroxyproline content as a measure of fibrosis (C). Fibrosis was measured by quantifying hydroxyproline levels in the tissues and normalizing to the numbers of eggs deposited in the liver. Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in three separate experiments.
Figure 5 Inflammation and fibrosis are exacerbated in S. mansoni infected Retnla−/− mice. (A) Control WT C57BL/6 mice (N = 19 wk 9, N = 7 wk 12) and Retnla−/− (N = 17 wk 9, N = 8 wk 12) mice were infected with 30–35 S. mansoni cercariae percutaneously. Mice were sacrificed at weeks 9 and 12 post infection and liver RNA specimens were prepared individually for real-time RT-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. In separate studies, the livers of S. mansoni infected mice were analyzed on wk 9 (WT N = 19, KO N = 17), 12 (WT N = 7, KO N = 8), and 25 (WT N = 10, KO N = 8) to evaluate the size of granulomas (Mean granuloma volume±SEM) as a measure of inflammation (B) and hydroxyproline content as a measure of fibrosis (C). Fibrosis was measured by quantifying hydroxyproline levels in the tissues and normalizing to the numbers of eggs deposited in the liver. Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in three separate experiments.CC0 · PubMed Central
Figure 6 Retnla−/− mice are more resistant to Nippostrongylus brasiliensis infection. (A) Lung samples from Retnla−/− mice infected with 500 N. brasiliensis larvae (L3) were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×20. (B) Analysis of control WT (N = 5) and Retnla−/− (N = 6) mice inoculated subcutaneously with 500 N. brasiliensis L3 and killed on day 12 after infection to assess adult worm recovery. (C) Control WT (N = 5, d4 and d7 and N = 10, d12) and Retnla−/− (N = 7, d4, N = 5, d7, and N = 10, d12) mice infected with 500 N. brasiliensis L3 larvae and killed on day 4, 7, and 12 after inoculation to assess adult worm recovery. (D) N. brasiliensis fecal eggs/worm day 7 post-infection (N = 5 each). (E) Peribrochiolar inflammation was scored on day 4 (WT N = 5, KO N = 7) and 7 (N = 5) post-infection (score 1–4). (F) Serum was isolated on day 7 and 12 post-inoculation and the amount of sIL-13Rα2 was quantified by ELISA in WT (N = 5) and Retnla−/− mice (N = 5) and reported as the average±SEM. Statistically significant differences and the corresponding p values are noted in all relevant figures. Similar results were obtained in two separate experiments.
Figure 6 Retnla−/− mice are more resistant to Nippostrongylus brasiliensis infection. (A) Lung samples from Retnla−/− mice infected with 500 N. brasiliensis larvae (L3) were snap frozen and embedded in OCT. In situ Retnla expression was evaluated by LacZ reporter activity (blue precipitate) in frozen tissue sections exposed to β-galactosidase substrate, X-gal. Original magnification ×20. (B) Analysis of control WT (N = 5) and Retnla−/− (N = 6) mice inoculated subcutaneously with 500 N. brasiliensis L3 and killed on day 12 after infection to assess adult worm recovery. (C) Control WT (N = 5, d4 and d7 and N = 10, d12) and Retnla−/− (N = 7, d4, N = 5, d7, and N = 10, d12) mice infected with 500 N. brasiliensis L3 larvae and killed on day 4, 7, and 12 after inoculation to assess adult worm recovery. (D) N. brasiliensis fecal eggs/worm day 7 post-infection (N = 5 each). (E) Peribrochiolar inflammation was scored on day 4 (WT N = 5, KO N = 7) and 7 (N = 5) post-infection (score 1–4). (F) Serum was isolated on day 7 and 12 post-inoculation and the amount of sIL-13Rα2 was quantified by ELISA in WT (N = 5) and Retnla−/− mice (N = 5) and reported as the average±SEM. Statistically significant differences and the corresponding p values are noted in all relevant figures. Similar results were obtained in two separate experiments.CC0 · PubMed Central
Figure 7 Th2 cytokine responses increase in N. brasiliensis-infected Retnla−/− mice. WT (N = 5/time point) and Retnla−/− (N = 5/time point) mice were inoculated subcutaneously with 500 N. brasiliensis L3 and the lungs were removed on day 7 and 12 after infection. The lungs were analyzed individually for Retnla, Il25, Il4, Ccl11 (Eotaxin), Il13, Il5, Muc5ac, and Gob5 mRNA by real-time quantitative PCR. Fold changes (Mean±SEM) are based on comparisons of infected mice with naive mice. Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in two separate experiments.
Figure 7 Th2 cytokine responses increase in N. brasiliensis-infected Retnla−/− mice. WT (N = 5/time point) and Retnla−/− (N = 5/time point) mice were inoculated subcutaneously with 500 N. brasiliensis L3 and the lungs were removed on day 7 and 12 after infection. The lungs were analyzed individually for Retnla, Il25, Il4, Ccl11 (Eotaxin), Il13, Il5, Muc5ac, and Gob5 mRNA by real-time quantitative PCR. Fold changes (Mean±SEM) are based on comparisons of infected mice with naive mice. Statistically significant differences and the corresponding p values are noted in the figures. Similar results were obtained in two separate experiments.CC0 · PubMed Central
Figure 8 Retnla suppresses S. mansoni egg-induced Th2 responses. (A) Naïve and i.p. egg sensitized and challenged (secondary) WT (N = 5/time point) and Retnla−/− (N = 5/time point) mice were sacrificed on day 7 post i.v. egg-challenge. Right lobe RNA specimens were prepared individually for real-time PCR analysis of Retnla, Il4, Il5, and Il13. Gene expression (Mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Statistically significant differences and the corresponding p values are noted in the panels. (B) Lung leukocytes were isolated, separated, counted and cultured with PMA, Ionomycin and Brefeldin A for 3 hrs and analyzed for ex-vivo cytokine production. Total number of IL-4, IL-5, and IFN-γ producing CD4+ T cells in the lung leukocyte preparation are shown for individual mice. The number of IFN-γ producing non-CD4+ T cells was also included (bottom panel). (C) Magnitude of cytokine production by CD4+ T cells displayed as the geometric mean of fluorescence intensity. Statistically significant differences are shown. All experiments were repeated twice with similar results.
Figure 8 Retnla suppresses S. mansoni egg-induced Th2 responses. (A) Naïve and i.p. egg sensitized and challenged (secondary) WT (N = 5/time point) and Retnla−/− (N = 5/time point) mice were sacrificed on day 7 post i.v. egg-challenge. Right lobe RNA specimens were prepared individually for real-time PCR analysis of Retnla, Il4, Il5, and Il13. Gene expression (Mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. Statistically significant differences and the corresponding p values are noted in the panels. (B) Lung leukocytes were isolated, separated, counted and cultured with PMA, Ionomycin and Brefeldin A for 3 hrs and analyzed for ex-vivo cytokine production. Total number of IL-4, IL-5, and IFN-γ producing CD4+ T cells in the lung leukocyte preparation are shown for individual mice. The number of IFN-γ producing non-CD4+ T cells was also included (bottom panel). (C) Magnitude of cytokine production by CD4+ T cells displayed as the geometric mean of fluorescence intensity. Statistically significant differences are shown. All experiments were repeated twice with similar results.CC0 · PubMed Central
Figure 9 Retnla is induced by IL-4/IL-13 and inhibited by IFN-γ. (A) Splenocytes were harvested from mice sufficient (HET, +/−) or deficient (KO, −/−) in Retnla 12 days after i.p. sensitization with 5000 viable S. mansoni eggs. Cells were stimulated with media, SEA (25 µg/ml) or ConA (1 µg/ml) in duplicate for 72 h at 37°C at which time supernatants were harvested and tested for IL-4 by ELISA. (B) Separate groups of SEA stimulated cells were also treated with PBS or rRelma (0.5 µg/ml) and examined for IL-4 (bars show Means±SD). (C) WT C57BL/6, IL-13KO, IFN-γ KO, IL-13/IFN-γKO, IL-4KO, IL-4/IL-13KO, and IL-4/IL-13/IFN-γ KO mice were infected with 30–35 S. mansoni cercariae and liver mRNA was isolated on wk 9 post-infection and prepared individually for real-time RT-PCR analysis of Retnla. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. The results from individual mice are shown. (D) Model depicting the role of Retnla in the regulation of Th2-driven inflammation, fibrosis and immunity to GI nematode infection. Retnla is induced by IL-4 and IL-13 and inhibits the Th2 effector response.
Figure 9 Retnla is induced by IL-4/IL-13 and inhibited by IFN-γ. (A) Splenocytes were harvested from mice sufficient (HET, +/−) or deficient (KO, −/−) in Retnla 12 days after i.p. sensitization with 5000 viable S. mansoni eggs. Cells were stimulated with media, SEA (25 µg/ml) or ConA (1 µg/ml) in duplicate for 72 h at 37°C at which time supernatants were harvested and tested for IL-4 by ELISA. (B) Separate groups of SEA stimulated cells were also treated with PBS or rRelma (0.5 µg/ml) and examined for IL-4 (bars show Means±SD). (C) WT C57BL/6, IL-13KO, IFN-γ KO, IL-13/IFN-γKO, IL-4KO, IL-4/IL-13KO, and IL-4/IL-13/IFN-γ KO mice were infected with 30–35 S. mansoni cercariae and liver mRNA was isolated on wk 9 post-infection and prepared individually for real-time RT-PCR analysis of Retnla. Gene expression (mean±SEM) is expressed as the fold-increase over naïve WT controls after normalization to HPRT. The results from individual mice are shown. (D) Model depicting the role of Retnla in the regulation of Th2-driven inflammation, fibrosis and immunity to GI nematode infection. Retnla is induced by IL-4 and IL-13 and inhibits the Th2 effector response.CC0 · PubMed Central

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  1. NG Sandler, 2003, Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair., J Immunol, 171, 3655, 10.4049/jimmunol.171.7.3655 · DOI
  2. AL Mora, 2006, Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis., Am J Respir Cell Mol Biol, 35, 466, 10.1165/rcmb.2006-0121OC · DOI
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Metadata

Authors
Pesce, J. T., Ramalingam, T. R., Wilson, M. S., Mentink-Kane, M. M., Thompson, R. W., Cheever, A. W., Urban, J. F., & Wynn, T. A.
Affiliations
  • National Institutes of Health (US)
  • Biomedical Research Institute (US)
  • Agricultural Research Service (US)
Corresponding author
Wynn, Thomas A.
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2009-04-17
Volume
5
Issue
4
Pages
e1000393
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1000393
PMC
PMC2663845
OpenAlex
W2087869886
Cited by
213
References
53
Citations by year
2026: 4 · 2025: 1 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 11 · 2019: 10 · 2018: 14 · 2017: 11 · 2016: 15 · 2015: 21 · 2014: 21 · 2013: 10 · 2012: 20
FWCI
14.83
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Regeneron Pharmaceuticals
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
Topics
  • Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
Keywords
Fizz1, Th2 immune response, helminthiasis, Schistosoma mansoni, Nippostrongylus brasiliensis, pulmonary granuloma, IL-4, IL-13, interferon-gamma, eosinophils, IgE, liver fibrosis, hepatosplenic schistosomiasis, intestinal nematode infection, granulomatous inflammation
MeSH terms
Animals, Eosinophils, Granuloma, Immunity, Innate, Interferon-gamma, Lung Diseases, Parasitic, Mice, Inbred C57BL, Nippostrongylus, Pulmonary Fibrosis, Schistosoma mansoni, Schistosomiasis mansoni, Interleukin-4, Strongylida Infections, Th2 Cells, Interleukin-13, Intercellular Signaling Peptides and Proteins, Mice

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