Ontogenetic regulation of leukocyte recruitment in mouse yolk sac vessels

Abstract

• Leukocyte recruitment is ontogentically regulated during fetal life.• A new intravital imaging model of leukocyte recruitment has been established in the mouse.In adult mammals, leukocyte recruitment follows a well-defined cascade of adhesion events enabling leukocytes to leave the circulatory system and transmigrate into tissue. Currently, it is unclear whether leukocyte recruitment proceeds in a similar fashion during fetal development. Considering the fact that the incidence of neonatal sepsis increases dramatically with decreasing gestational age in humans, we hypothesized that leukocyte recruitment may be acquired only late during fetal ontogeny. To test this, we developed a fetal intravital microscopy model in pregnant mice and, using LysEGFP (neutrophil reporter) mice, investigated leukocyte recruitment during fetal development. We show that fetal blood neutrophils acquire the ability to roll and adhere on inflamed yolk sac vessels during late fetal development, whereas at earlier embryonic stages (before day E15), rolling and adhesion were essentially absent. Accordingly, flow chamber experiments showed that fetal EGFP 1 blood cells underwent efficient adhesion only when they were harvested on or after E15. Fluorescence-activated cell sorter analysis on EGFP 1 fetal blood cells revealed that surface expression of CXCR2 and less pronounced P-selectin glycoprotein ligand-1 (PSGL-1) begin to increase only late in fetal life. Taken together, our findings demonstrate that inflammation-induced leukocyte recruitment is ontogenetically regulated and enables efficient neutrophil trafficking only during late fetal life. (Blood. 2013;121(21):e118-e128)

Leukocyte recruitment in preterm and term infants

“…Similar observations have been described for other adhesion molecules such as ICAM-1/-2, VCAM-1, VLA4, and PSGL-1 [29, 31, 38, 39]. Although fetal expression of the majority of adhesion molecules is low when compared to term infants and adults [11, 26, 36], others, like CXCR2, PECAM-1, and VE-cadherin (and LFA-1), are equally expressed in premature and mature neonates and adults (Table 2) [29, 31, 37]. …”

“…After extravasation, the neutrophil follows chemokine gradients through the tissue to the point of damage/inflammation. Developmental alterations of adhesion molecule expression are indicated by footnotes as follows (fetal/premature levels were compared to those of adults): ( a ) L-selectin - reduced [26, 33, 37, 45, 46] and unchanged [47], E-selectin - reduced [29, 31, 38], P-selectin - reduced [29, 34, 38, 39]; ( b ) PSGL-1 - reduced [29, 31, 36]; ( c ) Mac-1 - reduced [26, 31, 36], unchanged [30, 33], and increased [37]; ( d ) LFA-1 - reduced [26, 45] and unchanged [30, 31, 36, 37]; ( e ) ICAM-1 - reduced [29, 31, 38]; ( f ) CXCR2 - unchanged [31] …”

“…Sperandio et al showed in vivo that neutrophil rolling and adhesion in murine yolk sac vessels is strongly reduced at early gestational ages and increases throughout gestation [29]. These observations were validated in human preterm and term leukocytes in vitro using flow chamber experiments as a rule-in/rule-out approach [30].…”

“…Several studies describe significantly reduced neutrophil transmigration and chemotaxis in neonates compared to adults [11, 29, 32]. Notably, cellular immunity of preterm infants matures slower and later than in term infants [11].…”

Invadopodia: a new therapeutic target to block cancer metastasis

“…In contrast to immune cells, we found that cancer cells do not roll, but exclusively employ active migration, reinforcing the idea that cancer and immune cells use distinct extravasation mechanisms [1,2,9]. Within 4-6 h after arriving in the capillaries, cancer cells initiate the formation of a single dominant protrusion that crosses the endothelial layer into the extravascular stroma.…”