Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

Abstract

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrinmediated adhesion Highlights d Loss of WRC in macrophages impairs phagocytosis, spreading, and (de)adhesion d WRC loss of function perturbs integrin activation and FAK/ paxillin phosphorylation d Arp2/3 complex and WRC functions on integrin adhesion are at least partly separable

Molecular Tuning of Actin Dynamics in Leukocyte Migration as Revealed by Immune-Related Actinopathies

“…Megakaryocytes from WASPdeficient mice displayed impaired CXCL12-evoked migration upon interaction with fibrillar collagen I (95). This combined T cells: defective membrane ruffling, loss of lamellipodia, reduced F-actin density at the leading edge with abnormal puncta, spikes, and blebs, ↓ migratory velocity (43,44), lack of polarization (45) B cells: aberrant morphology, defective directional migration when exposed to CCL19 gradient (44) Neutrophils: ↓ velocity, ↓ directional persistence, misdirected competing leading edges (43), abnormal distribution of F-actinat at the leading edge instead of the lamellipodium (45) Mice neutrophils and macrophages: defective migration (46,47), spiky shape (47) and defect in actin polymerisation (46), accumulation within and near blood vessels and defective migration in 3D chemokine gradient (47) Mice DC: lack of lamellipodia, ↑ speed, ↑ directional persistance and migration speed paths in 3D collagen gels (48) Zebrafish neutrophils: defective migration (45) adhesion and motility defect was shown to be associated with an inability of these cells to assemble actin-rich podosomes (see chapter 4 for detailed description). As a result of these defects, WASP-deficient megakaryocytes appeared to shed platelets ectopically within the BM space, which might explain the severe thrombocytopenia characteristic of WAS.…”

“…Interestingly, neutrophils from XLN mice exhibit an increased infiltrating capacity with a competitive advantage over WT neutrophils in mixed bone marrow chimeras. The study of HEM1-null macrophages and neutrophils suggested an impaired migration in vitro ( 46 , 47 ). More precisely, the knock-down of nckap1l , the gene encoding for HEM1, in zebrafish was responsible for a defective neutrophil migration after tail injury along with a decrease in circulating neutrophils ( 45 ).…”

“…Recently, 3 additional actin-related deficiencies have been added to the list of actinopathies affecting TEM of immune cells: MKL1 ( 49 ), HEM1 ( 47 ) and ERM ( 53 ) deficiencies. MKL1 deficiency led to poor adhesion and TEM of patient neutrophils ( 49 ).…”

“…MKL1 deficiency led to poor adhesion and TEM of patient neutrophils ( 49 ). Studies of HEM1 deficiency in murine models showed drastic accumulation of HEM1-deficient myeloid cells both within and near the blood vessels ( 47 ). It is unclear, however, which step of immune cell migration (trans-endothelial or interstitial) might be affected in HEM1-deficient cells.…”

“…To date, studies of virtually all actin-related IEIs revealed defects in immune cell migration in vitro ( Table 1 ). In contrast, data on ability of immune cells to migrate in vivo is available for a handful of gene defects: DOCK8 ( 37 ), DOCK2 ( 35 ), NCKAP1L ( 47 ) and MYH9 ( 55 ). Deficiency of DOCK8, an atypical immune system specific guanine nucleotide-exchange factor, is probably one of the best described actin-related IEIs affecting interstitial migration of immune cells.…”