The role of Four-and-a-half LIM domain protein 2 in 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. <em>In vivo</em>, DCs continuously acquire Ag in the periphery and migrate to draining LNs, 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.<br /> 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, <em>in vivo</em>, FHL2-/- BMDCs showed increased migration toward lymphoid organs. FHL2-/- BMDCs increased the expression of S1P receptor 1, 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.