Human neutrophil antigen‐3a antibodies induce neutrophil stiffening and conformational activation of CD11b without shedding of L‐selectin

Berthold, T.; Glaubitz, Michael; Muschter, Stefan; Groß, Stefan; Palankar, Raghavendra; Reil, Angelika; Helm, Christiane A.; Bakchoul, Tamam; Schwertz, Hansjörg; Bux, Jürgen; Greinacher, Andreas; Delcea, Mihaela

doi:10.1111/trf.13299

Cited by 5 publications

(3 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CD13 has long been implicated in pro-adhesive events such as aggregation [72,73] and invasiveness [74], while CR3 (CD11b/CD18) is well-known for its adhesive properties and activation in response to the stimulation of other receptors. For example, CD11b activation triggered by human neutrophil antigen 3a auto-antibodies leads to neutrophil accumulation in the pulmonary microvasculature of some blood transfusion recipients, causing severe transfusion-related acute lung injury [75]. This suggests that CD13 and CR3 may participate in the same adhesion events during inflammation-related transendothelial migration.…”

Section: Discussionmentioning

confidence: 99%

Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18

Díaz-Alvarez,

Martínez-Sánchez,

Gray

et al. 2023

Biomolecules

View full text Add to dashboard Cite

The β2 integrin CD11b/CD18, also known as complement receptor 3 (CR3), and the moonlighting protein aminopeptidase N (CD13), are two myeloid immune receptors with overlapping activities: adhesion, migration, phagocytosis of opsonized particles, and respiratory burst induction. Given their common functions, shared physical location, and the fact that some receptors can activate a selection of integrins, we hypothesized that CD13 could induce CR3 activation through an inside-out signaling mechanism and possibly have an influence on its membrane expression. We revealed that crosslinking CD13 on the surface of human macrophages not only activates CR3 but also influences its membrane expression. Both phenomena are affected by inhibitors of Src, PLCγ, Syk, and actin polymerization. Additionally, after only 10 min at 37 °C, cells with crosslinked CD13 start secreting pro-inflammatory cytokines like interferons type 1 and 2, IL-12p70, and IL-17a. We integrated our data with a bioinformatic analysis to confirm the connection between these receptors and to suggest the signaling cascade linking them. Our findings expand the list of features of CD13 by adding the activation of a different receptor via inside-out signaling. This opens the possibility of studying the joint contribution of CD13 and CR3 in contexts where either receptor has a recognized role, such as the progression of some leukemias.

show abstract

Section: Discussionmentioning

confidence: 99%

Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18

Díaz-Alvarez,

Martínez-Sánchez,

Gray

et al. 2023

Biomolecules

View full text Add to dashboard Cite

show abstract

“…iC3b-opsonized pathogens are recognized and phagocytosed through CR3. CR3-mediated phagocytosis is synergistically enhanced by other receptors, for example, Francisella tularensis is internalized in concert by CR3 and CR1, each binding their own ligands on the surface of the bacterium ( 59 ), or Borrelia burgdorferi , whereby internalization by human macrophages is orchestrated by CR3, CD14 and scavenger receptors ( 60 ). As CD13 also acts as co-receptor to other phagocytic receptors like FcγRs and Mannose receptors ( 26, 61 ), this may also be the case for its functional interaction with CR3.…”

Section: Discussionmentioning

confidence: 99%

Inside-out Signalling From Aminopeptidase N (CD13) To Complement Receptor 3 (CR3, CD11b/CD18)

Díaz-Alvarez

Martinez-Sanchez

Gray

et al. 2021

Preprint

View full text Add to dashboard Cite

Upon ligand engagement, certain receptors can activate an integrin through a mechanism called inside-out signalling. This phenomenon prepares the cell for the next steps of the process it will perform. CR3 (Complement receptor 3), the most abundant β2 integrin in monocytes and macrophages, and CD13 (aminopeptidase N) are two immune receptors with overlapping activities: adhesion, phagocytosis of opsonized particles, and respiratory burst induction. They can be found together in functional signalling microdomains, or lipid rafts, on the surface of human leukocytes. Thus, given their common functions, shared physical location and the fact that some phagocytic and adhesion receptors activate a selection of integrins, we hypothesized that CD13 could activate CR3 through an inside-out signalling mechanism. To test this hypothesis, we first ascertained the activation of CR3 after CD13 crosslinking in human monocyte-derived macrophages. We used an integrated analysis of bioinformatics and experimental data to suggest two possible signalling cascades that could explain the phenomenon. Finally, we show that the non-receptor tyrosine kinase Syk is a key attenuator of this pathway. Our results demonstrated that, even in the absence of canonical signalling motifs, and despite having a noticeably short cytoplasmic tail (7-10 amino acids), CD13 was capable of triggering an inside-out signalling cascade, adding a new function to those already known for this moonlighting protein.

show abstract

“…Autoimmune disease [12,40,47,48] Thrombosis Cardiovascular disease [49] Transfusion-related acute lung injury (TRALI) Acute injury [50] Trauma/Vascular injury Acute injury [51][52][53] Wiskott Aldrich syndrome Genetic disorder [54,55]…”

Section: Disease or Disorder Category Referencesmentioning

confidence: 99%

Targeting Neutrophil β2-Integrins: A Review of Relevant Resources, Tools, and Methods

Conley

Sheats

2023

Biomolecules

View full text Add to dashboard Cite

Neutrophils are important innate immune cells that respond during inflammation and infection. These migratory cells utilize β2-integrin cell surface receptors to move out of the vasculature into inflamed tissues and to perform various anti-inflammatory responses. Although critical for fighting off infection, neutrophil responses can also become dysregulated and contribute to disease pathophysiology. In order to limit neutrophil-mediated damage, investigators have focused on β2-integrins as potential therapeutic targets, but so far these strategies have failed in clinical trials. As the field continues to move forward, a better understanding of β2-integrin function and signaling will aid the design of future therapeutics. Here, we provide a detailed review of resources, tools, experimental methods, and in vivo models that have been and will continue to be utilized to investigate the vitally important cell surface receptors, neutrophil β2-integrins.

show abstract

Human neutrophil antigen‐3a antibodies induce neutrophil stiffening and conformational activation of CD11b without shedding of L‐selectin

Abstract: Accumulation of neutrophils in the pulmonary microvasculature during severe TRALI is likely mediated by increased rigidity and CD11b-mediated adhesion of neutrophils leading to retention of neutrophils.

Cited by 5 publications

References 45 publications

Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18

Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18

Inside-out Signalling From Aminopeptidase N (CD13) To Complement Receptor 3 (CR3, CD11b/CD18)

Targeting Neutrophil β2-Integrins: A Review of Relevant Resources, Tools, and Methods

Contact Info

Product

Resources

About