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Anti-HMGB1 neutralizing antibody ameliorates neutrophilic airway inflammation by suppressing dendritic cell-mediated Th17 polarization.
- Source :
-
Mediators of inflammation [Mediators Inflamm] 2014; Vol. 2014, pp. 257930. Date of Electronic Publication: 2014 May 15. - Publication Year :
- 2014
-
Abstract
- We demonstrate that high mobility group box 1 protein (HMGB1) directs Th17 skewing by regulating dendritic cell (DC) function. First, our in vitro studies reveal that recombinant HMGB1 (rHMGB1) activates myeloid DCs to produce IL-23 in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretion in vivo by using a murine model of neutrophilic asthma induced by ovalbumin (OVA) plus lipopolysaccharide (LPS). Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C(+) APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.
- Subjects :
- Adoptive Transfer
Animals
Asthma immunology
Bronchoalveolar Lavage Fluid
CD11c Antigen metabolism
CD4-Positive T-Lymphocytes cytology
Coculture Techniques
Cytokines metabolism
Female
Flow Cytometry
Inflammation
Interleukin-23 metabolism
Lipopolysaccharides chemistry
Lung immunology
Lymphocytes immunology
Mice
Mice, Inbred BALB C
Neutrophils cytology
Neutrophils immunology
Ovalbumin chemistry
Phenotype
Antibodies, Neutralizing immunology
Dendritic Cells cytology
HMGB1 Protein immunology
Th17 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1466-1861
- Volume :
- 2014
- Database :
- MEDLINE
- Journal :
- Mediators of inflammation
- Publication Type :
- Academic Journal
- Accession number :
- 24959003
- Full Text :
- https://doi.org/10.1155/2014/257930