A Role for Leukocyte-derived IL-1RA in DC Homeostasis Revealed by Increased Susceptibility of IL-1RA-deficient Mice to Cutaneous Leishmaniasis

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2011 Apr 29

PMID 21525884

Citations 10

Authors

Kordula Kautz-Neu

Susanna Lopez Kostka

Stephanie Dinges

Yoichiro Iwakura

Mark C Udey

Esther von Stebut

Affiliations

Soon will be listed here.

Abstract

Dendritic cell (DC)-derived IL-1α/β plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania. DCs from susceptible BALB/c mice produce less IL-1α/β when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA(-/-) BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA(-/-) mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-γ production by antigen-specific T cells. We determined that IL-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1α/β signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen.

Citing Articles

Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity.

Farias Amorim C, Lovins V, Singh T, Novais F, Harris J, Lago A Sci Transl Med. 2023; 15(718):eadh1469.

PMID: 37851822 PMC: 10627035. DOI: 10.1126/scitranslmed.adh1469.

Host-Directed Therapies for Cutaneous Leishmaniasis.

Novais F, Farias Amorim C, Scott P Front Immunol. 2021; 12:660183.

PMID: 33841444 PMC: 8032888. DOI: 10.3389/fimmu.2021.660183.

Interleukin-1 as Innate Mediator of T Cell Immunity.

Van Den Eeckhout B, Tavernier J, Gerlo S Front Immunol. 2021; 11:621931.

PMID: 33584721 PMC: 7873566. DOI: 10.3389/fimmu.2020.621931.

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis.

Farias Amorim C, Novais F, Nguyen B, Misic A, Carvalho L, Carvalho E Sci Transl Med. 2019; 11(519).

PMID: 31748229 PMC: 7068779. DOI: 10.1126/scitranslmed.aax4204.

Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus.

Ritprajak P, Kaewraemruaen C, Hirankarn N Cells. 2019; 8(10).

PMID: 31640263 PMC: 6830089. DOI: 10.3390/cells8101291.

References

von Stebut E, Udey M . Requirements for Th1-dependent immunity against infection with Leishmania major. Microbes Infect. 2004; 6(12):1102-9. DOI: 10.1016/j.micinf.2004.05.024. View

Lichtman A, Chin J, Schmidt J, Abbas A . Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci U S A. 1988; 85(24):9699-703. PMC: 282842. DOI: 10.1073/pnas.85.24.9699. View

Fitzgerald A, LeClercq S, Yan A, Homik J, Dinarello C . Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum. 2005; 52(6):1794-803. DOI: 10.1002/art.21061. View

Jacobs T, Andra J, Gaworski I, Graefe S, Mellenthin K, Kromer M . Complement C3 is required for the progression of cutaneous lesions and neutrophil attraction in Leishmania major infection. Med Microbiol Immunol. 2004; 194(3):143-9. DOI: 10.1007/s00430-004-0229-y. View

Shortman K, Liu Y . Mouse and human dendritic cell subtypes. Nat Rev Immunol. 2002; 2(3):151-61. DOI: 10.1038/nri746. View

Weaver C, Hawrylowicz C, UNANUE E . T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988; 85(21):8181-5. PMC: 282391. DOI: 10.1073/pnas.85.21.8181. View

Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y . IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A. 2003; 100(10):5986-90. PMC: 156313. DOI: 10.1073/pnas.1035999100. View

von Stebut E, Metz M, Milon G, Knop J, Maurer M . Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1alpha /beta released from neutrophils recruited by mast cell-derived TNFalpha. Blood. 2002; 101(1):210-5. DOI: 10.1182/blood-2002-03-0921. View

von Stebut E, Belkaid Y, Jakob T, Sacks D, Udey M . Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity. J Exp Med. 1998; 188(8):1547-52. PMC: 2213412. DOI: 10.1084/jem.188.8.1547. View

10.

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A . Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med. 2000; 191(2):313-20. PMC: 2195765. DOI: 10.1084/jem.191.2.313. View

11.

Ribeiro-Gomes F, Otero A, Gomes N, Moniz-de-Souza M, Cysne-Finkelstein L, Arnholdt A . Macrophage interactions with neutrophils regulate Leishmania major infection. J Immunol. 2004; 172(7):4454-62. DOI: 10.4049/jimmunol.172.7.4454. View

12.

Huber M, Beuscher H, Rohwer P, Kurrle R, Rollinghoff M, Lohoff M . Costimulation via TCR and IL-1 receptor reveals a novel IL-1alpha-mediated autocrine pathway of Th2 cell proliferation. J Immunol. 1998; 160(9):4242-7. View

13.

Belkaid Y, Mendez S, Lira R, Kadambi N, Milon G, Sacks D . A natural model of Leishmania major infection reveals a prolonged "silent" phase of parasite amplification in the skin before the onset of lesion formation and immunity. J Immunol. 2000; 165(2):969-77. DOI: 10.4049/jimmunol.165.2.969. View

14.

Sacks D, Noben-Trauth N . The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol. 2002; 2(11):845-58. DOI: 10.1038/nri933. View

15.

Filippi C, Hugues S, Cazareth J, Julia V, Glaichenhaus N, Ugolini S . CD4+ T cell polarization in mice is modulated by strain-specific major histocompatibility complex-independent differences within dendritic cells. J Exp Med. 2003; 198(2):201-9. PMC: 2194066. DOI: 10.1084/jem.20021893. View

16.

Nigg A, Zahn S, Ruckerl D, Holscher C, Yoshimoto T, Ehrchen J . Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice. J Immunol. 2007; 178(11):7251-8. DOI: 10.4049/jimmunol.178.11.7251. View

17.

Moll H . Dendritic cells and host resistance to infection. Cell Microbiol. 2003; 5(8):493-500. DOI: 10.1046/j.1462-5822.2003.00291.x. View

18.

Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J . Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. 2005; 201(9):1479-86. PMC: 2213182. DOI: 10.1084/jem.20050473. View

19.

Shibuya K, Robinson D, Zonin F, Hartley S, Macatonia S, Somoza C . IL-1 alpha and TNF-alpha are required for IL-12-induced development of Th1 cells producing high levels of IFN-gamma in BALB/c but not C57BL/6 mice. J Immunol. 1998; 160(4):1708-16. View

20.

Kostka S, Dinges S, Griewank K, Iwakura Y, Udey M, von Stebut E . IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice. J Immunol. 2009; 182(5):3039-46. PMC: 2658650. DOI: 10.4049/jimmunol.0713598. View