Four-and-a-Half LIM Domain Protein 2 Is a Novel Regulator of Sphingosine 1-Phosphate Receptor 1 in CCL19-Induced Dendritic Cell Migration

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.