Abstract
We identified the four-and-a-half LIM domain protein 2 (FHL2) as a novel regulator of CCL19-induced dendritic cell (DC) migration. Initiation of migration is a hallmark of DC function and plays a central role in the induction and regulation of immune responses. In vivo, DCs continuously acquire Ag in the periphery and migrate to draining lymph nodes, under the influence of local environmental chemotactic factors like CCL19/21 or sphingosine 1-phosphate (S1P). We investigated the role of S1P- and RhoA-regulated FHL2 in this process. We found reduced nuclear localization of FHL2 in mature bone marrow-derived DCs (BMDCs), compared with immature BMDCs, following stimulation with CCL19. Furthermore, in vitro-generated murine FHL2(-/-) BMDCs displayed a significantly increased migratory speed, directionality, and migratory persistence toward the chemokine CCL19 compared with wild-type BMDCs. Moreover, in vivo, FHL2(-/-) BMDCs showed increased migration toward lymphoid organs. FHL2(-/-) BMDCs increased the expression of S1PR1, which was associated with greater Rac activation. An S1PR1 antagonist and knock-down of S1PR1 abrogated the increased migratory speed of FHL2(-/-) BMDCs. Our results identify FHL2 as an important novel regulator of DC migration via regulation of their sensitivity toward environmental migratory cues like S1P and CCL19.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / enzymology
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Movement / genetics
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Cell Movement / immunology*
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Cell Nucleus / genetics
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Cell Nucleus / immunology
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Cell Nucleus / metabolism
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Cells, Cultured
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Chemokine CCL19 / physiology*
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Dendritic Cells / cytology*
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Immunophenotyping
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LIM-Homeodomain Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Muscle Proteins / deficiency
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Muscle Proteins / genetics
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Muscle Proteins / physiology*
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Receptors, Lysosphingolipid / metabolism*
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Receptors, Lysosphingolipid / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Sphingosine-1-Phosphate Receptors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Up-Regulation / genetics
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Up-Regulation / immunology
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rac GTP-Binding Proteins / metabolism
Substances
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Ccl19 protein, mouse
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Chemokine CCL19
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Fhl2 protein, mouse
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Homeodomain Proteins
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LIM-Homeodomain Proteins
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Muscle Proteins
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Receptors, Lysosphingolipid
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S1PR1 protein, human
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Sphingosine-1-Phosphate Receptors
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Transcription Factors
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rac GTP-Binding Proteins