Pathophysiology of leukocyte–tissue interactions
Introduction
Cells in metazoans are engaged in a regulatory network of intercellular signaling pathways that control homeostasis as well as the response to pathogenic stress. Cell–cell and cell–extracellular matrix (ECM) adhesion is a prominent component of such pathways. Leukocytes are no exception, albeit their distinctive feature is to engage adhesion receptors only occasionally and in a highly regulated fashion.
Although leukocytes display a heterogeneous array of adhesion molecules, most of which are shared with other somatic cells, integrins can be viewed as a paradigm for adhesion structures involved in leukocyte–tissue interactions. This review focuses mainly on integrins expressed by leukocytes, with emphasis on the role they play in the reciprocal interaction of leukocytes with their surrounding tissues. Through paradigmatic examples of such interactions, some common issues will be addressed: the signals controlling leukocyte integrin activation and function at the interface between a leukocyte and other cells or tissue components; the specificity of integrin engagement during the various stages of leukocyte–tissue interaction; the subcellular localization of integrins and how it affects their function and signaling properties; and finally, the downstream events triggered by leukocyte integrin clustering and their consequences for the activation, survival, differentiation and effector function of leukocytes (Figure 1).
Section snippets
Leukocyte–endothelium interactions
Leukocyte recruitment from the blood to lymphoid and non-lymphoid tissues occurs via a multi-step process controlled by integrated chemoattractant-dependent signals and adhesive events [1, 2]. First, circulating leukocytes tether and roll along the vessel wall by establishing transient selectin-mediated interactions with endothelial cells. This initial contact allows leukocytes to recognize chemoattractants (mostly chemokines) presented on the apical surface of the endothelium that trigger
Endothelial consequences of leukocyte adhesion
The cross-talk between leukocytes and ECs is highly relevant in the context of leukocyte transendothelial migration (TEM), which can occur through either a paracellular, junctional or a transcellular, transcytotic route. EC junctional molecules, including PECAM-1 [20, 21], junction adhesion molecules (JAMs) [22, 23] and CD99 [24] are involved in paracellular diapedesis. Although membrane molecule interactions are critical, transient inter-EC gaps must be formed in order to permit leukocyte
Leukocyte–interstitial matrix interactions
Sequential engagement of β2 integrins at the leukocyte–EC interface and of β1 integrins during basement membrane crossing represent classical examples of short-range interactions of limited duration [36]. Later in the process, leukocyte integrins are engaged in more sustained interactions with interstitial ECM components, which may affect inflammatory cell activation, differentiation and survival besides providing positional information. In the case of monocytes, the key integrin molecules
Genetic programs induced by integrin signaling in leukocytes
It has been shown that human blood monocytes undergo differentiation to macrophages upon interaction with the ECM-rich environment of extravascular tissue. Most genes require simultaneous engagement of integrins and growth factor receptors to be significantly modulated [46]. The use of global gene expression profiling techniques offers a quantitative and qualitative means to examine synergy between growth factors and integrins. Several groups have used such approaches to assess the contribution
Leukocyte survival by integrin engagement
Unlike most somatic cells, leukocytes have evolved the ability to survive in the absence of adhesion to substrate. This is probably accomplished by the constitutive expression of anti-apoptotic genes such as Bcl-2 or Bcl-xL, which is a feature of several mature leukocyte lineages and is developmentally regulated [49]. Nevertheless, according to the prevailing paradigm, neutrophils are short-lived cells that undergo spontaneous apoptosis within 24 hours of their release from the bone marrow and
Leukocyte activation and differentiation by integrin engagement
Integrins regulate gene expression through the activation of transcription factors. Engagement of β2 integrins by a broad repertoire of ligands generates outside-in signals leading to inflammatory cell activation and induction of genes encoding cytokines and tissue factors but, as mentioned above, evidence for the in vivo relevance of this process is scanty [53]. Shi et al. explored this issue elegantly after identifying the forkhead transcription factor Foxp1 as a downstream target of αM/β2
Leuokcyte proliferation by integrin engagement
The relevance of integrin-dependent cell adhesion in cell cycle progression of leukocytes has been most extensively investigated in T lymphocytes. T cells are highly dependent on adhesive interactions for functional activation throughout their antigen-driven maturation process, as the T cell receptor has evolved to recognize antigen in a cell-associated form [58]. Naïve T cells engage in prolonged, integrin-dependent contacts with APCs to receive mitogenic or lineage-specific differentiation
Leukocytes within the inflammatory milieu
Recently transmigrated leukocytes are exposed and respond to a host of mediators released in the early stage of an inflammatory response. The earliest inflammatory signals include growth factors released by degranulating platelets, peptides cleaved from bacterial proteins (fMLF), endotoxin (LPS) and a cocktail of proinflammatory molecules released by resident macrophages and mast cells, such as vasoactive amines, cytokines and chemokines. Surprisingly, this complex microenvironment evokes
Conclusions
By exerting interdependent functions such as shear-stress-resistant adhesion and transmembrane signaling, integrins play a prominent role in the dynamic interaction of leukocytes with surrounding tissues. When assessing the contribution of integrins to the pathophysiology of leukocyte behavior, it has been difficult to discriminate between a direct effect of integrin signaling and an indirect effect resulting from the essential role of these receptors in adhesion and migration. This is
References and recommended reading
Papers cited in this review have been indicated as
• of special interest
•• of outstanding interest
Acknowledgements
This work is supported by the Italian Ministry of University and Research (MIUR) and the EU Network of Excellence “Targeting Cell Migration in Chronic Inflammation” (MAIN, FP6-502935, R. Pardi, Coordinator) to R. Pardi and by grants from NIH (R01 HL43331) and the Raymond and Beverly Sackler Foundation to J. R. Bender.
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