IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection

Bishwas Shrestha, Dahui You, Jordy Saravia, David Siefker, Sridhar Jaligama, Greg I. Lee, Asmaa A. Sallam, Jeffrey N. Harding, Stephania Cormier

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL- 4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.

Original languageEnglish (US)
Pages (from-to)153-161
Number of pages9
JournalJournal of Leukocyte Biology
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2017

Fingerprint

Interleukin-4 Receptors
Respiratory Syncytial Virus Infections
Myeloid Cells
Dendritic Cells
Respiratory Syncytial Viruses
Newborn Infant
Lung
Down-Regulation
CD4 Antigens
Bronchiolitis
Adoptive Transfer
Antisense Oligonucleotides
Mucus
Asthma
Inflammation
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

Shrestha, B., You, D., Saravia, J., Siefker, D., Jaligama, S., Lee, G. I., ... Cormier, S. (2017). IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection. Journal of Leukocyte Biology, 102(1), 153-161. https://doi.org/10.1189/jlb.4A1216-536R

IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection. / Shrestha, Bishwas; You, Dahui; Saravia, Jordy; Siefker, David; Jaligama, Sridhar; Lee, Greg I.; Sallam, Asmaa A.; Harding, Jeffrey N.; Cormier, Stephania.

In: Journal of Leukocyte Biology, Vol. 102, No. 1, 01.07.2017, p. 153-161.

Research output: Contribution to journalArticle

Shrestha, B, You, D, Saravia, J, Siefker, D, Jaligama, S, Lee, GI, Sallam, AA, Harding, JN & Cormier, S 2017, 'IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection', Journal of Leukocyte Biology, vol. 102, no. 1, pp. 153-161. https://doi.org/10.1189/jlb.4A1216-536R
Shrestha, Bishwas ; You, Dahui ; Saravia, Jordy ; Siefker, David ; Jaligama, Sridhar ; Lee, Greg I. ; Sallam, Asmaa A. ; Harding, Jeffrey N. ; Cormier, Stephania. / IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection. In: Journal of Leukocyte Biology. 2017 ; Vol. 102, No. 1. pp. 153-161.
@article{ded289be25194326b575c82c1dca5e49,
title = "IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection",
abstract = "Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL- 4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.",
author = "Bishwas Shrestha and Dahui You and Jordy Saravia and David Siefker and Sridhar Jaligama and Lee, {Greg I.} and Sallam, {Asmaa A.} and Harding, {Jeffrey N.} and Stephania Cormier",
year = "2017",
month = "7",
day = "1",
doi = "10.1189/jlb.4A1216-536R",
language = "English (US)",
volume = "102",
pages = "153--161",
journal = "Journal of Leukocyte Biology",
issn = "0741-5400",
publisher = "FASEB",
number = "1",

}

TY - JOUR

T1 - IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection

AU - Shrestha, Bishwas

AU - You, Dahui

AU - Saravia, Jordy

AU - Siefker, David

AU - Jaligama, Sridhar

AU - Lee, Greg I.

AU - Sallam, Asmaa A.

AU - Harding, Jeffrey N.

AU - Cormier, Stephania

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL- 4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.

AB - Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL- 4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.

UR - http://www.scopus.com/inward/record.url?scp=85021717713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021717713&partnerID=8YFLogxK

U2 - 10.1189/jlb.4A1216-536R

DO - 10.1189/jlb.4A1216-536R

M3 - Article

VL - 102

SP - 153

EP - 161

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

IS - 1

ER -