Abstract
Background: Bacterial cowshed isolates are allergy protective in mice; however, the underlying mechanisms are largely unknown. We examined the ability of . Lactococcus lactis G121 to prevent allergic inflammatory reactions. Objective: We sought to identify the ligands and pattern recognition receptors through which . L lactis G121 confers allergy protection. Methods: L lactis G121-induced cytokine release and surface expression of costimulatory molecules by untreated or inhibitor-treated (bafilomycin and cytochalasin D) human monocyte-derived dendritic cells (moDCs), bone marrow-derived mouse dendritic cells (BMDCs), and moDC/naive CD4+ T-cell cocultures were analyzed by using ELISA and flow cytometry. The pathology of ovalbumin-induced acute allergic airway inflammation after adoptive transfer of BMDCs was examined by means of microscopy. Results: L lactis G121-treated murine BMDCs and human moDCs released TH1-polarizing cytokines and induced TH1 T cells. Inhibiting phagocytosis and endosomal acidification in BMDCs or moDCs impaired the release of TH1-polarizing cytokines, costimulatory molecule expression, and T-cell activation on L lactis G121 challenge. In vivo allergy protection mediated by L lactis G121 was dependent on endosomal acidification in dendritic cells (DCs). Toll-like receptor (Tlr) 13 -/- BMDCs showed a weak response to L lactis G121 and were unresponsive to its RNA. The TH1-polarizing activity of L lactis G121-treated human DCs was blocked by TLR8-specific inhibitors, mediated by L lactis G121 RNA, and synergistically enhanced by activation of nucleotide-binding oligomerization domain-containing protein (NOD) 2. Conclusion: Bacterial RNA is the main driver of . L lactis G121-mediated protection against experimentally induced allergy and requires both bacterial uptake by DCs and endosomal acidification. In mice . L lactis G121 RNA signals through TLR13; however, the most likely intracellular receptor in human subjects is TLR8.
| Original language | English (US) |
|---|---|
| Journal | Journal of Allergy and Clinical Immunology |
| DOIs | |
| State | Accepted/In press - Sep 23 2015 |
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Keywords
- Allergy protection
- Bacterial RNA
- Dendritic cells
- Endosomal acidification
- Lactococcus lactis G121
- Pattern recognition receptor
- Toll-like receptor 13
- Toll-like receptor 8
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Endosomal recognition of Lactococcus lactis G121 and its RNA by dendritic cells is key to its allergy-protective effects. / Stein, Karina; Brand, Stephanie; Jenckel, André; Sigmund, Anna; Chen, Zhijian James; Kirschning, Carsten J.; Kauth, Marion; Heine, Holger.
In: Journal of Allergy and Clinical Immunology, 23.09.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endosomal recognition of Lactococcus lactis G121 and its RNA by dendritic cells is key to its allergy-protective effects
AU - Stein, Karina
AU - Brand, Stephanie
AU - Jenckel, André
AU - Sigmund, Anna
AU - Chen, Zhijian James
AU - Kirschning, Carsten J.
AU - Kauth, Marion
AU - Heine, Holger
PY - 2015/9/23
Y1 - 2015/9/23
N2 - Background: Bacterial cowshed isolates are allergy protective in mice; however, the underlying mechanisms are largely unknown. We examined the ability of . Lactococcus lactis G121 to prevent allergic inflammatory reactions. Objective: We sought to identify the ligands and pattern recognition receptors through which . L lactis G121 confers allergy protection. Methods: L lactis G121-induced cytokine release and surface expression of costimulatory molecules by untreated or inhibitor-treated (bafilomycin and cytochalasin D) human monocyte-derived dendritic cells (moDCs), bone marrow-derived mouse dendritic cells (BMDCs), and moDC/naive CD4+ T-cell cocultures were analyzed by using ELISA and flow cytometry. The pathology of ovalbumin-induced acute allergic airway inflammation after adoptive transfer of BMDCs was examined by means of microscopy. Results: L lactis G121-treated murine BMDCs and human moDCs released TH1-polarizing cytokines and induced TH1 T cells. Inhibiting phagocytosis and endosomal acidification in BMDCs or moDCs impaired the release of TH1-polarizing cytokines, costimulatory molecule expression, and T-cell activation on L lactis G121 challenge. In vivo allergy protection mediated by L lactis G121 was dependent on endosomal acidification in dendritic cells (DCs). Toll-like receptor (Tlr) 13 -/- BMDCs showed a weak response to L lactis G121 and were unresponsive to its RNA. The TH1-polarizing activity of L lactis G121-treated human DCs was blocked by TLR8-specific inhibitors, mediated by L lactis G121 RNA, and synergistically enhanced by activation of nucleotide-binding oligomerization domain-containing protein (NOD) 2. Conclusion: Bacterial RNA is the main driver of . L lactis G121-mediated protection against experimentally induced allergy and requires both bacterial uptake by DCs and endosomal acidification. In mice . L lactis G121 RNA signals through TLR13; however, the most likely intracellular receptor in human subjects is TLR8.
AB - Background: Bacterial cowshed isolates are allergy protective in mice; however, the underlying mechanisms are largely unknown. We examined the ability of . Lactococcus lactis G121 to prevent allergic inflammatory reactions. Objective: We sought to identify the ligands and pattern recognition receptors through which . L lactis G121 confers allergy protection. Methods: L lactis G121-induced cytokine release and surface expression of costimulatory molecules by untreated or inhibitor-treated (bafilomycin and cytochalasin D) human monocyte-derived dendritic cells (moDCs), bone marrow-derived mouse dendritic cells (BMDCs), and moDC/naive CD4+ T-cell cocultures were analyzed by using ELISA and flow cytometry. The pathology of ovalbumin-induced acute allergic airway inflammation after adoptive transfer of BMDCs was examined by means of microscopy. Results: L lactis G121-treated murine BMDCs and human moDCs released TH1-polarizing cytokines and induced TH1 T cells. Inhibiting phagocytosis and endosomal acidification in BMDCs or moDCs impaired the release of TH1-polarizing cytokines, costimulatory molecule expression, and T-cell activation on L lactis G121 challenge. In vivo allergy protection mediated by L lactis G121 was dependent on endosomal acidification in dendritic cells (DCs). Toll-like receptor (Tlr) 13 -/- BMDCs showed a weak response to L lactis G121 and were unresponsive to its RNA. The TH1-polarizing activity of L lactis G121-treated human DCs was blocked by TLR8-specific inhibitors, mediated by L lactis G121 RNA, and synergistically enhanced by activation of nucleotide-binding oligomerization domain-containing protein (NOD) 2. Conclusion: Bacterial RNA is the main driver of . L lactis G121-mediated protection against experimentally induced allergy and requires both bacterial uptake by DCs and endosomal acidification. In mice . L lactis G121 RNA signals through TLR13; however, the most likely intracellular receptor in human subjects is TLR8.
KW - Allergy protection
KW - Bacterial RNA
KW - Dendritic cells
KW - Endosomal acidification
KW - Lactococcus lactis G121
KW - Pattern recognition receptor
KW - Toll-like receptor 13
KW - Toll-like receptor 8
UR - http://www.scopus.com/inward/record.url?scp=84996570097&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84996570097&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2016.06.018
DO - 10.1016/j.jaci.2016.06.018
M3 - Article
C2 - 27544739
AN - SCOPUS:84996570097
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
ER -