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Endogenous IL-13 plays a crucial role in liver granuloma maturation during Leishmania donovani infection, independent of IL-4Rα-responsive macrophages and neutrophils.

McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J - J. Infect. Dis. (2011)

Bottom Line: This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels.Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy.Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

ABSTRACT
Previous studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

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Granuloma maturation in L. donovani–infected wild-type and IL-13-/- mice at days 14 (A) and 35 (B) postinfection. The data are means ± standard errors for 1 of 4 independent experiments. *P < .05 and **P < .01 wild-type versus IL-13-/-. Photomicrographs showing the hepatic granuloma response in two L. donovani–infected mice, wild-type (C) and IL-13-/- (D), at day 35 postinfection. Wild-type mice show well-developed mature granulomas (arrows) surrounding a core of infected Kupffer cells, whereas IL-13-/- mice show abrogated granuloma development characterized by the presence of immature granulomas and amastigotes within the cytoplasm of Kupffer cells at day 35 postinfection (arrows). Magnification x400.
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fig2: Granuloma maturation in L. donovani–infected wild-type and IL-13-/- mice at days 14 (A) and 35 (B) postinfection. The data are means ± standard errors for 1 of 4 independent experiments. *P < .05 and **P < .01 wild-type versus IL-13-/-. Photomicrographs showing the hepatic granuloma response in two L. donovani–infected mice, wild-type (C) and IL-13-/- (D), at day 35 postinfection. Wild-type mice show well-developed mature granulomas (arrows) surrounding a core of infected Kupffer cells, whereas IL-13-/- mice show abrogated granuloma development characterized by the presence of immature granulomas and amastigotes within the cytoplasm of Kupffer cells at day 35 postinfection (arrows). Magnification x400.

Mentions: We also assessed granuloma maturation in livers from wild-type and IL-13-/- mice over this period (Figures 2A and 2B). We scored granulomas as described previously [16]: infected Kupffer cells (parasitized macrophages), immature granuloma (consisting of T cells and monocytes surrounding infected Kupffer cells), mature (developed), or sterile (parasite-free) granuloma. IL-13-/- BALB/c mice showed normal early inflammatory responses, with the formation of immature granulomas with similar frequency as wild-type mice on day 14 postinfection (Figure 2A). Whereas approximately 60% of the inflammatory foci had progressed to mature or sterile granulomas in wild-type mice at day 35 postinfection (Figures 2B–C), granulomas failed to mature in IL-13-/- mice (Figures 2B–D) and the histological profile was similar to that of day 14. Because the overall granulomatous response at day 35 is indicative of a good healing response [16], which is reflected by the reduction in parasite burdens in wild-type mice, these data suggest that host-protective granulomatous responses were inhibited in IL-13-/- mice.


Endogenous IL-13 plays a crucial role in liver granuloma maturation during Leishmania donovani infection, independent of IL-4Rα-responsive macrophages and neutrophils.

McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J - J. Infect. Dis. (2011)

Granuloma maturation in L. donovani–infected wild-type and IL-13-/- mice at days 14 (A) and 35 (B) postinfection. The data are means ± standard errors for 1 of 4 independent experiments. *P < .05 and **P < .01 wild-type versus IL-13-/-. Photomicrographs showing the hepatic granuloma response in two L. donovani–infected mice, wild-type (C) and IL-13-/- (D), at day 35 postinfection. Wild-type mice show well-developed mature granulomas (arrows) surrounding a core of infected Kupffer cells, whereas IL-13-/- mice show abrogated granuloma development characterized by the presence of immature granulomas and amastigotes within the cytoplasm of Kupffer cells at day 35 postinfection (arrows). Magnification x400.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3105032&req=5

fig2: Granuloma maturation in L. donovani–infected wild-type and IL-13-/- mice at days 14 (A) and 35 (B) postinfection. The data are means ± standard errors for 1 of 4 independent experiments. *P < .05 and **P < .01 wild-type versus IL-13-/-. Photomicrographs showing the hepatic granuloma response in two L. donovani–infected mice, wild-type (C) and IL-13-/- (D), at day 35 postinfection. Wild-type mice show well-developed mature granulomas (arrows) surrounding a core of infected Kupffer cells, whereas IL-13-/- mice show abrogated granuloma development characterized by the presence of immature granulomas and amastigotes within the cytoplasm of Kupffer cells at day 35 postinfection (arrows). Magnification x400.
Mentions: We also assessed granuloma maturation in livers from wild-type and IL-13-/- mice over this period (Figures 2A and 2B). We scored granulomas as described previously [16]: infected Kupffer cells (parasitized macrophages), immature granuloma (consisting of T cells and monocytes surrounding infected Kupffer cells), mature (developed), or sterile (parasite-free) granuloma. IL-13-/- BALB/c mice showed normal early inflammatory responses, with the formation of immature granulomas with similar frequency as wild-type mice on day 14 postinfection (Figure 2A). Whereas approximately 60% of the inflammatory foci had progressed to mature or sterile granulomas in wild-type mice at day 35 postinfection (Figures 2B–C), granulomas failed to mature in IL-13-/- mice (Figures 2B–D) and the histological profile was similar to that of day 14. Because the overall granulomatous response at day 35 is indicative of a good healing response [16], which is reflected by the reduction in parasite burdens in wild-type mice, these data suggest that host-protective granulomatous responses were inhibited in IL-13-/- mice.

Bottom Line: This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels.Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy.Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

ABSTRACT
Previous studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

Show MeSH
Related in: MedlinePlus