The molecular basis of leukocyte recruitment and its deficiencies

Schmidt, Sarah; Moser, Markus; Sperandio, Markus

doi:10.1016/j.molimm.2012.11.006

Cited by 190 publications

(157 citation statements)

References 148 publications

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“…Human pathology indicates the vital necessity of all the above steps as any disturbance of the migration, superoxide production, opsonization or granule production results in serious diseases with repeated, often life-threatening infections [30,46,52,100,112].…”

Section: Introductionmentioning

confidence: 99%

Changing world of neutrophils

Tímár

Lörincz

Ligeti

2013

Pflugers Arch - Eur J Physiol

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Section: Introductionmentioning

confidence: 99%

Changing world of neutrophils

Tímár

Lörincz

Ligeti

2013

Pflugers Arch - Eur J Physiol

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“…The multistep adhesion cascade defines the increasingly adhesive steps leukocytes make with the endothelium to exit the circulation and enter the surrounding microenvironment (4). Each step of the cascade [tethering, rolling, slow rolling, firm adhesion, and transendothelial migration (TEM)] critically depends on cell adhesion molecules expressed on both leukocytes and endothelial cells.…”

mentioning

confidence: 99%

“…Such cell adhesion molecules have been identified and characterized to act in a sequential and interdependent manner. The molecular mechanism driving leukocyte integrin function during the multistep adhesion cascade is relatively well defined (4)(5)(6). In contrast, mechanisms underpinning the regulation of nonintegrin receptors are only beginning to emerge.…”

mentioning

confidence: 99%

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro

Rzeniewicz

Newe

Gallardo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

103

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L-selectin is a cell adhesion molecule that tethers free-flowing leukocytes from the blood to luminal vessel walls, facilitating the initial stages of their emigration from the circulation toward an extravascular inflammatory insult. Following shear-resistant adhesion to the vessel wall, L-selectin has frequently been reported to be rapidly cleaved from the plasma membrane (known as ectodomain shedding), with little knowledge of the timing or functional consequence of this event. Using advanced imaging techniques, we observe L-selectin shedding occurring exclusively as primary human monocytes actively engage in transendothelial migration (TEM). Moreover, the shedding was localized to transmigrating pseudopods within the subendothelial space. By capturing monocytes in midtransmigration, we could monitor the subcellular distribution of L-selectin and better understand how ectodomain shedding might contribute to TEM. Mechanistically, L-selectin loses association with calmodulin (CaM; a negative regulator of shedding) specifically within transmigrating pseudopods. In contrast, L-selectin/ CaM interaction remained intact in nontransmigrated regions of monocytes. We show phosphorylation of L-selectin at Ser 364 is critical for CaM dissociation, which is also restricted to the transmigrating pseudopod. Pharmacological or genetic inhibition of L-selectin shedding significantly increased pseudopodial extensions in transmigrating monocytes, which potentiated invasive behavior during TEM and prevented the establishment of front/back polarity for directional migration persistence once TEM was complete. We conclude that L-selectin shedding directly regulates polarity in transmigrated monocytes, which affirms an active role for this molecule in driving later stages of the multistep adhesion cascade.

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“…Selectins bind to complex carbohydrates expressed on specific glycoproteins. The importance of the selectin ligands is illustrated by the leukocyte adhesion deficiency syndrome II, in which patients lack proper formation of selectin ligands and suffer from life-threatening episodes of recurrent infections (32,36). The best-characterized selectin ligand is CD162, which binds to both P-and E-selectin (24).…”

Section: Discussionmentioning

confidence: 99%

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

Zhang

Song

Wang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Zhang S, Song L, Wang Y, Herwald H, Thorlacius H. Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury. Am J Physiol Lung Cell Mol Physiol 305: L756 -L763, 2013. First published September 13, 2013 doi:10.1152/ajplung.00220.2013.-Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 proteinprovoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by Ͼ54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections. adhesion; chemokines; inflammation and leukocyte CLINICAL MANIFESTATIONS OF Streptococcus pyogenes infections vary from uncomplicated cases to severe and fatal conditions, such as streptococcal toxic shock syndrome (STSS), which is associated with a mortality exceeding 50% (7, 15). Despite significant investigative efforts, management of patients with STSS is largely restricted to antibiotics and supportive care, which is partly due to an incomplete understanding of the basic pathophysiology in STSS. S. pyogenes express several different virulence factors, including M proteins, of which there are more than 80 different serotypes described in the literature (15,26). The M1 serotype of Streptococcus pyogenes is most commonly linked to STSS (7). Numerous studies have documented that M1 protein is a powerful stimulator of innate immune cells, such as monocytes (26) and neutrophils (15). In addition, the M1 protein has the capacity to induce formation of cytokines (26), chemokines (9), and tissue factor (25), which all contribute to M1 protein-induced edema formation and tissue damage in the lung. Several studies have shown that lung failure is an insidious feature in STSS patie...

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The molecular basis of leukocyte recruitment and its deficiencies

Cited by 190 publications

References 148 publications

Changing world of neutrophils

Changing world of neutrophils

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

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