Four-and-a-half LIM domain protein 2 is a novel regulator of sphingosine 1-phosphate receptor 1 in CCL19-induced dendritic cell migration
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Four-and-a-half LIM domain protein 2 is a novel regulator of sphingosine 1-phosphate receptor 1 in CCL19-induced dendritic cell migration. / König, Katharina; Diehl, Linda; Rommerscheidt-Fuss, Ursula; Golletz, Carsten; Quast, Thomas; Kahl, Philip; Kolanus, Waldemar; Knolle, Percy; Buettner, Reinhard; Heukamp, Lukas C.
In: J IMMUNOL, Vol. 185, No. 3, 01.08.2010, p. 1466-75.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Four-and-a-half LIM domain protein 2 is a novel regulator of sphingosine 1-phosphate receptor 1 in CCL19-induced dendritic cell migration
AU - König, Katharina
AU - Diehl, Linda
AU - Rommerscheidt-Fuss, Ursula
AU - Golletz, Carsten
AU - Quast, Thomas
AU - Kahl, Philip
AU - Kolanus, Waldemar
AU - Knolle, Percy
AU - Buettner, Reinhard
AU - Heukamp, Lukas C
PY - 2010/8/1
Y1 - 2010/8/1
N2 - 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.
AB - 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.
KW - Animals
KW - Bone Marrow Cells
KW - Cell Differentiation
KW - Cell Movement
KW - Cell Nucleus
KW - Cells, Cultured
KW - Chemokine CCL19
KW - Dendritic Cells
KW - Homeodomain Proteins
KW - Immunophenotyping
KW - LIM-Homeodomain Proteins
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Muscle Proteins
KW - Receptors, Lysosphingolipid
KW - Signal Transduction
KW - Transcription Factors
KW - Up-Regulation
KW - rac GTP-Binding Proteins
U2 - 10.4049/jimmunol.0903449
DO - 10.4049/jimmunol.0903449
M3 - SCORING: Journal article
C2 - 20592280
VL - 185
SP - 1466
EP - 1475
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 3
ER -