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.

Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection

“…In addition, the secretion of IL-12 in Beclin-1 +/À BMDCs is inhibited after activation, which is likely to impair their MHC-I cross-presenting ability because IL-12 has been reported to enhance DC MHC-I cross-presentation. 48 In summary, we found that H1N1 virus infection induces autophagy in DCs. Autophagy-deficient DCs exhibited a less mature phenotype and reduced production of IL-6, TNF-a, IFN-b, IL-12p70 and IFN-c cytokines upon H1N1 infection.…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…49 Additionally, studies focusing on miR-146a-mediated repression of IL-12p70 production in TLR9-triggered DCs identified Notch1 as a target of miR-146a. 92 However, there may be other proteins and miRNAs involved in this process, which requires further investigation.…”

MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha

“…miRNAs have been shown to play critical roles in the regulation of diverse biological processes, including development, differentiation, carcinogenesis, infection and immunity. [15][16][17][18][19][20][21] Since their initial observation, approximately 1000 miRNA sequences have been identified in mammals, but the detailed biological functions of a large number of miRNAs remain elusive. Previous reports have shown that some miRNAs, such as miR-146a and miR-155, are induced during virus infection and participate in the regulation of the innate antiviral response.…”