Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Abstract

Eosinophilic inflammation is a characteristic feature of asthma. Integrins are highly versatile cellular receptors that regulate extravasation of eosinophils from the postcapillary segment of the bronchial circulation to the airway wall and airspace. Such movement into the asthmatic lung is described as a sequential, multistep paradigm, whereby integrins on circulating eosinophils become activated, eosinophils tether in flow and roll on bronchial endothelial cells, integrins on rolling eosinophils become further activated as a result of exposure to cytokines, eosinophils arrest firmly to adhesive ligands on activated endothelium, and eosinophils transmigrate to the airway in response to chemoattractants. Eosinophils express seven integrin heterodimeric adhesion molecules: alpha4beta1 (CD49d/29), alpha6beta1 (CD49f/29), alphaMbeta2 (CD11b/18), alphaLbeta2 (CD11a/18), alphaXbeta2 (CD11c/18), alphaDbeta2 (CD11d/18), and alpha4beta7 (CD49d/beta7). The role of these integrins in eosinophil recruitment has been elucidated by major advances in the understanding of integrin structure, integrin function, and modulators of integrins. Such findings have been facilitated by cellular experiments of eosinophils in vitro, studies of allergic asthma in humans and animal models in vivo, and crystal structures of integrins. Here, we elaborate on how integrins cooperate to mediate eosinophil movement to the asthmatic airway. Antagonists that target integrins or the effectors that regulate integrins of eosinophils represent potentially promising therapies in the treatment of asthma.

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

“…The highly dynamic F-actin-rich protrusions contain large amounts of integrins, and actin-binding and actin-severing proteins such as gelsolin. The major function of gelsolin is to rapidly depolymerize F-actin, and thus gelsolin sustains the dynamics of protrusions and withdrawal which is essential for directed locomotion [24,25]. Adhesion sites contain clustered integrins that transmit mechanical forces in the migration process and are involved in signaling cascades essential for cell survival and morphogenesis [26].…”

“…The highly dynamic F-actin-rich protrusions contain large amounts of integrins, and actin-binding and actin-severing proteins such as gelsolin. The major function of gelsolin is to rapidly depolymerize F-actin, and thus gelsolin sustains the dynamics of protrusions and withdrawal which is essential for directed locomotion [24,25].…”

Integrins as therapeutic targets: lessons and opportunities

“…Natalizumab, a humanized mAb specific for the α 4 integrin subunit was found to be effective in the treatment of multiple sclerosis 5,[34][35][36][37][38][39] and also for the inflammatory bowel disorder Crohn's disease 6 . Inhibitors of α 4 integrins have been effective in animal models of asthma but none have been effective in Phase II trials 40 .…”

A role for MC3R in modulating lung inflammation

“…The host-inflammatory response is driven by pro-inflammatory mediators including the cytokines IL-1β, TNF-α and IL-8 (CXCL8), upregulation of adhesion molecules and proteolytic enzymes leading to the migration of leukocytes to the site of inflammation for TH1 responses [3]. Whilst for TH2 responses in the asthmatic lung activation of integrins on circulating eosinophils followed by tethering and rolling on bronchial endothelial cells [4] with increases in IL-4 and IL-5 leading to further activation and subsequent transmigration [5]. To aid in the resolution of this response a number of endogenous modulators of inflammation are produced including annexin 1 [6], galectin [7], lipoxins [8] and melanocortins [9,10] and these have been shown to inhibit leukocyte trafficking and help prevent tissue damage.…”