β2 Integrin Signaling Cascade in Neutrophils: More Than a Single Function

Abstract

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of β2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of β2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two β2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting β2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease.

Intravascular Crawling of Patrolling Monocytes: A Lèvy-Like Motility for Unique Search Functions?

“…How do PMo perceive that they have to increase the frequency of Lèvy-like walks for a more efficient search, especially for small targets, and how do they re-adapt their arsenal of adhesion and chemokine receptors to this type of movement? PMo show an amoeboid morphology when crawling in the slow phase of Lèvy-like walk suggestive of signals driven by b2 integrin interactions as shown in neutrophils (47,48). This is supported by the presence of a few Lèvy-like tracks in steadystate in the lung and kidney capillaries, territories with abundant endothelial CX3CL1, upregulator of b2 integrin affinity (3,19).…”

Immunology of Acute and Chronic Wound Healing

“…A study in murine models demonstrated that cutaneous wounds heal faster in neutrophil-depleted mice compared with controls, concluding that excessive recruitment of neutrophils at the wound site may delay wound healing [ 61 ]. Macrophages can phagocyte neutrophils through β2 integrins after completion of DAMP clearance [ 54 , 62 ]. Furthermore, matricellular protein CCN1 also plays an important role in neutrophil clearance.…”

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

“…CR3 is primarily expressed in leukocytes like neutrophils, monocytes, macrophages, and dendritic cells ( 9 ). Two main physiological roles have been described for CR3.…”

“…The events triggered by either signalling pathway generally recruit distinct effectors, for example, following engagement of the extracellular effector Mindin, CR3 outside-in signalling results in the activation of the MAPK pathway and translocation of NF-κb into the nucleus ( 16 ). In contrast, stimulation of G-protein coupled receptors results in the transition of CR3 from its low- affinity to its high-affinity state via an inside-out signalling pathway that includes the activation of phospholipases Cβ2 and Cβ3, and the calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (reviewed in ( 9 )). Some molecules can participate in both CR3 inside-out and outside-in signalling, including Rap1, RIAM, Talin, Kindlin and Syk ( 9, 17–20 ).…”

“…In contrast, stimulation of G-protein coupled receptors results in the transition of CR3 from its low- affinity to its high-affinity state via an inside-out signalling pathway that includes the activation of phospholipases Cβ2 and Cβ3, and the calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (reviewed in ( 9 )). Some molecules can participate in both CR3 inside-out and outside-in signalling, including Rap1, RIAM, Talin, Kindlin and Syk ( 9, 17–20 ).…”