Stay or Stray: Lpar1 regulates neutrophil retention and epidermal homeostasis in early zebrafish development

Abstract

Neutrophils are the most abundant myeloid cells in the vertebrate innate immune system and play a crucial role in host defense. Dysregulated release from hematopoietic tissue or excessive recruitment to inflamed sites is associated with immunopathologies, including chronic inflammation and recurrent infections. Lysophosphatidic acid (LPA) is a bioactive lipid that signals through a family of G protein-coupled receptors (LPAR1-6). Among these, LPA-LPAR1 signaling is activated in inflamed tissues and is known to modulate neutrophil infiltration during inflammatory responses. However, its role in neutrophil dynamics during early development remains unclear. Here, we report a novel function of Lpar1 in regulating neutrophil behavior during early zebrafish development. In Lpar1-deficient embryos, we observed a significant increase in neutrophil dispersal from the caudal hematopoietic tissue (CHT) at 3 days post-fertilization (dpf), with most dispersed neutrophils infiltrating the skin and contributing to elevated inflammatory signaling. Prior to dispersal, Lpar1-deficient embryos exhibited increased apoptosis of superficial epidermal cells and reduced expression of cxcl12a, a key retention signal for neutrophils in the CHT. Together, these findings highlight an essential role for Lpar1 in maintaining neutrophil retention and epidermal homeostasis during early development, thereby limiting inappropriate inflammation. SUMMARY STATEMENTThis work identifies a new role for a known inflammatory receptor in coordinating immune cell retention and skin stability during early development.