Fer Kinase Limits Neutrophil Chemotaxis toward End Target Chemoattractants

Abstract

Neutrophil recruitment and directional movement toward chemotactic stimuli are important processes in innate immune responses. This study examines the role of Fer kinase in neutrophil recruitment and chemotaxis to various chemoattractants in vitro and in vivo. Mice targeted with a kinase-inactivating mutation (FerDR/DR) or wild type (WT) were studied using time-lapse intravital microscopy to examine leukocyte recruitment and chemotaxis in vivo. In response to keratinocyte-derived cytokine, no difference in leukocyte chemotaxis was observed between WT and FerDR/DR mice. However, in response to the chemotactic peptide WKYMVm, a selective agonist of the formyl peptide receptor, a 2-fold increase in leukocyte emigration was noted in FerDR/DR mice (p < 0.05). To determine whether these defects were due to Fer signaling in the endothelium or other nonhematopoietic cells, bone marrow chimeras were generated. WKYMVm-induced leukocyte recruitment in chimeric mice (WT bone marrow to FerDR/DR recipients or vice versa) was similar to WT mice, suggesting that Fer kinase signaling in both leukocytes and endothelial cells serves to limit chemotaxis. Purified FerDR/DR neutrophils demonstrated enhanced chemotaxis toward end target chemoattractants (WKYMVm and C5a) compared with WT using an under-agarose gel chemotaxis assay. These defects were not observed in response to intermediate chemoattractants (keratinocyte-derived cytokine, MIP-2, or LTB4). Increased WKYMVm-induced chemotaxis of FerDR/DR neutrophils correlated with sustained PI3K activity and reduced reliance on the p38 MAPK pathway compared with WT neutrophils. Together, these data identify Fer as a novel inhibitory kinase for neutrophil chemotaxis toward end target chemoattractants through modulation of PI3K activity.

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

“…Although no particular mechanism was described in this population study, it was suggested that FER could been implied in the regulation of host defense mechanisms along with preservation of epithelial and endothelial barrier function, which could explain many of its protective effects (12, 39–45). …”

The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm

“…In the resulting D743R mutant, FER and FERT proteins lack kinase activity, and the protein is unstable. Fer DR/DR mice show several defects, which implicate FER in growth factor signaling (Craig et al, 2001), hematopoiesis (Senis et al, 2003), tumorigenesis (Sangrar et al, 2015), regulation of the cytoskeleton (Sangrar et al, 2007;Xu et al, 2004) and inflammatory cell functions Khajah et al, 2013;McCafferty et al, 2002). Here, we used this murine model to evaluate the role of FER and FERT in the capacitation-associated increase of tyrosine phosphorylation.…”

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

“…ZBTB16 modulates autophagy by degrading Atg14 (35). MAFB is an important transcriptional factor for macrophage differentiation (36), and FER plays a role in neutrophil chemotaxis (37), both of which are involved in innate immunity and plausibly affect autophagy functions (38,39). Therefore, genes involved in autophagy and innate immunity are candidates for the development of Paneth cell defect in Japanese CD.…”