title: Activated apoptotic cells induce dendritic cell maturation via engagement of Toll-like receptor 4 (TLR4), dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN), and β2 integrins.
abstract: Dendritic cells (DCs) are professional antigen-presenting cells playing a central role in connecting innate and adaptive immunity. Maturation signals are, however, required for DCs to undergo phenotypic and functional changes to acquire a fully competent antigen-presenting capacity. We previously reported that activated apoptotic peripheral lymphocytes (ActApo) provide activation/maturation signals to human monocyte-derived DCs. In this paper, we have characterized the signaling pathways and molecules involved in ActApo-mediated DC maturation. We found that both cellular and supernatant fractions from ActApo are required for DC maturation signaling. ActApoSup-induced CD80 and CD86 expression was significantly blocked in the presence of neutralizing antibodies against tumor necrosis factor-α (TNF-α). Cell-cell contact-dependent signaling involved β2 integrins, dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), and TLR4 because ActApo-induced up-regulation of the maturation markers CD80 and CD86 was significantly inhibited in the presence of neutralizing antibodies against CD18, CD11a, CD11b, and DC-SIGN as well as TLR4. The role of TLR4 was further confirmed by silencing of TLR4 in DCs. In addition, the endogenous adjuvant effect exerted by activated apoptotic splenocytes (ActApoSp) was reduced after immunization with human serum albumin in TLR4(-/-) mice. We detected activation of multiple signaling pathways and transcription factors in DCs upon co-culture with ActApo, including p38, JNK, PI3K-Akt, Src family kinases, NFκB p65, and AP1 transcription factor family members c-Jun and c-Fos, demonstrating the complex interactions occurring between ActApo and DCs. These studies provide important mechanistic insight into the responses of DCs during encounter with cells undergoing immunogenic cell death.
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Pathak
authors.forename: Annette E
authors.initials: AE
authors.lastname: Sköld
authors.forename: Venkatramanan
authors.initials: V
authors.lastname: Mohanram
authors.forename: Catrine
authors.initials: C
authors.lastname: Persson
authors.forename: Ulrika
authors.initials: U
authors.lastname: Johansson
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Spetz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D018821:CD18 Antigens / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C483616:ICAM3 protein, human; C573564:ICAM3 protein, mouse; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse