Distinct Roles for the α and β Subunits in the Functions of Integrin αMβ2

Solovjov, Dmitry A.; Pluskota, Elżbieta; Plow, Edward F.

doi:10.1074/jbc.m406968200

Cited by 236 publications

(194 citation statements)

References 64 publications

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“…CD11b complexes with integrin beta‐2 to form the heterodimeric integrin α M β 2 , also known as complement receptor 3 (CR3), and is important for microglial adhesion, migration, and complement‐mediated pruning of synapses (Schafer et al., 2012; Solovjov et al., 2005). Increased CD11b with acute EtOH and acute stress suggests enhanced microglial activation to what has been called a hyperramified state associated with cytokine secretion and increased responsiveness or “priming,” but not the fully activated microglial bushy or phagocytic morphology activation states (Crews and Vetreno, 2016; He and Crews, 2008).…”

Section: Discussionmentioning

confidence: 99%

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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BackgroundCycles of alcohol and stress are hypothesized to contribute to alcohol use disorders. How this occurs is poorly understood, although both alcohol and stress activate the neuroimmune system—the immune molecules and cells that interact with the nervous system. The effects of alcohol and stress on the neuroimmune system are mediated in part by peripheral signaling molecules. Alcohol and stress both enhance immunomodulatory molecules such as corticosterone and endotoxin to impact neuroimmune cells, such as microglia, and may subsequently impact neurons. In this study, we therefore examined the effects of acute and chronic ethanol (EtOH) on the corticosterone, endotoxin, and microglial and neuronal response to acute stress.MethodsMale Wistar rats were treated intragastrically with acute EtOH and acutely stressed with restraint/water immersion. Another group of rats was treated intragastrically with chronic intermittent EtOH and acutely stressed following prolonged abstinence. Plasma corticosterone and endotoxin were measured, and immunohistochemical stains for the microglial marker CD11b and neuronal activation marker c‐Fos were performed.ResultsAcute EtOH and acute stress interacted to increase plasma endotoxin and microglial CD11b, but not plasma corticosterone or neuronal c‐Fos. Chronic EtOH caused a lasting sensitization of stress‐induced plasma endotoxin, but not plasma corticosterone. Chronic EtOH also caused a lasting sensitization of stress‐induced microglial CD11b, but not neuronal c‐Fos.ConclusionsThese results find acute EtOH combined with acute stress enhanced plasma endotoxin, as well as microglial CD11b in many brain regions. Chronic EtOH followed by acute stress also increased plasma endotoxin and microglial CD11b, suggesting a lasting sensitization to acute stress. Overall, these data suggest alcohol and stress interact to increase plasma endotoxin, resulting in enhanced microglial activation that could contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Walter

Vetreno

Crews

2017

Alcoholism Clin & Exp Res

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“…To determine whether CD11b is sufficient to render cells susceptible to LukAB, we next performed a gain-of-function experiment. It has been shown that HEK293T cells can support CD11b surface localization in the absence of CD18 (22). Therefore, we transiently transfected these cells with either a plasmid encoding CD11b or an empty plasmid, and CD11b surface levels were determined via flow cytometry (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mac-1 is expressed in all cells targeted by LukAB (9) including PMNs, macrophages, monocytes, and dendritic cells (28), and is involved in multiple cellular functions such as phagocytosis, cellular activation, cell-mediated killing, and chemotaxis (22,29). The prevalence of Mac-1 on these crucial immune cell types is exploited by multiple pathogens in addition to S. aureus, and may be a conserved method of targeting host phagocytes.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

DuMont

Yoong

Day

et al. 2013

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

193

279

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Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and celltype specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin's tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.toxin receptor | pore-forming cytotoxin

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“…The affinity between integrins and their ligands is regulated by divalent cations. [25][26][27] Notably, Mn 2+ is reported to largely promote the binding of ligands to integrins. Transduction efficiencies of an Ad35 vector expressing an enhanced green fluorescence protein (GFP) (Ad35GFP) in K562 cells were significantly reduced in the presence of EDTA (Figure 2a).…”

Section: Divalent Cations Are Required For Ad35 Vector-mediated Transmentioning

confidence: 99%

Interaction of penton base Arg-Gly-Asp motifs with integrins is crucial for adenovirus serotype 35 vector transduction in human hematopoietic cells

et al. 2007

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Most subgroup B adenoviruses (Ads), including adenovirus (Ad) serotype 35 (Ad35), bind to human CD46 as a receptor; however, the infection processes of subgroup B Ads following attachment to CD46 remain to be elucidated. Subgroup B Ads possess Arg-Gly-Asp (RGD) motifs in the penton base, similarly to subgroup C Ad serotypes 2 and 5. In this study, we examined the role of penton base RGD motifs in Ad35 vector-mediated transduction in human hematopoietic cells. Inhibition of interaction between integrins and the RGD motifs by divalent cation chelation and a synthetic RGD peptide reduced the transduction efficiencies of Ad35 vectors; however, the amounts of cell-associated vector DNA of Ad35 vectors at 4 or 37 1C were not decreased by divalent cation chelation or the RGD peptide. Mutation of penton base RGD motifs reduced the transduction efficiencies of Ad35 vectors, although the amounts of cell-associated vector DNA of Ad35 vectors at 4 or 37 1C were not altered by mutation of penton base RGD motifs in Ad35 vectors. Furthermore, preincubation with several types of anti-integrin antibodies significantly inhibited Ad35 vectormediated transduction. These results suggest that interaction between integrins and penton base RGD motifs plays a crucial role in Ad35 vector-mediated transduction in hematopoietic cells, probably in the post-internalization steps.

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Distinct Roles for the α and β Subunits in the Functions of Integrin αMβ2

Cited by 236 publications

References 64 publications

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

Interaction of penton base Arg-Gly-Asp motifs with integrins is crucial for adenovirus serotype 35 vector transduction in human hematopoietic cells

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