title: Integrin CD11b negatively regulates TLR9-triggered dendritic cell cross-priming by upregulating microRNA-146a.
abstract: Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that β2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-κB activation. Additionally, Notch1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs.
authors.affiliation: National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bai
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.forename: Jin
authors.initials: J
authors.lastname: Hou
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Chen
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D018664:Interleukin-12