Abstract
Recruitment of leucocytes such as neutrophils to the extravascular space is a critical step of the inflammation process and plays a major role in the development of various diseases including several cardiovascular diseases. Neutrophils themselves play a very active role in that process by sensing their environment and responding to the extracellular cues by adhesion and de-adhesion, cellular shape changes, chemotactic migration, and other effector functions of cell activation. Those responses are co-ordinated by a number of cell surface receptors and their complex intracellular signal transduction pathways. Here, we review neutrophil signal transduction processes critical for recruitment to the site of inflammation. The two key requirements for neutrophil recruitment are the establishment of appropriate chemoattractant gradients and the intrinsic ability of the cells to migrate along those gradients. We will first discuss signalling steps required for sensing extracellular chemoattractants such as chemokines and lipid mediators and the processes (e.g. PI3-kinase pathways) leading to the translation of extracellular chemoattractant gradients to polarized cellular responses. We will then discuss signal transduction by leucocyte adhesion receptors (e.g. tyrosine kinase pathways) which are critical for adhesion to, and migration through the vessel wall. Finally, additional neutrophil signalling pathways with an indirect effect on the neutrophil recruitment process, e.g. through modulation of the inflammatory environment, will be discussed. Mechanistic understanding of these pathways provide better understanding of the inflammation process and may point to novel therapeutic strategies for controlling excessive inflammation during infection or tissue damage.
Highlights
Neutrophils play a critical role in host defence against invading pathogens, but they are critical contributors to tissue damage in immune-mediated disease processes such as autoimmune or autoinflammatory diseases,[1,2,3] and they strongly contribute to various diseases of the cardiovascular system such as atherosclerosis,[4] myocardial infarction, stroke and ischaemia – reperfusion injury,[5,6,7] thrombosis,[8] as well as small vessel vasculitis.[9]
In contrast to mature neutrophils, E-selectin ligand 1 (ESL-1) is fundamentally important for homing of haematopoietic progenitor cells (HPCs) to the bone marrow indicating its differential role in various leucocyte subsets.[86]. Together these results suggest that ESL-1 is dispensable in neutrophils for transducing intracellular signals leading to the conformational change of LFA-1 into the intermediate affinity state allowing slow neutrophil rolling on ICAM-1
The stabilization of the high affinity conformation of the b2-integrins under flow conditions critically depends on mammalian actin binding protein 1 (mAbp1).83 In addition to induction of firm adhesion, mAbp1-deficient neutrophils are compromised in b2-integrin-dependent post-adhesion functions namely adhesion strengthening, spreading, and intraluminal crawling under flow conditions.[83]
Summary
Neutrophils play a critical role in host defence against invading pathogens, but they are critical contributors to tissue damage in immune-mediated disease processes such as autoimmune or autoinflammatory diseases,[1,2,3] and they strongly contribute to various diseases of the cardiovascular system such as atherosclerosis,[4] myocardial infarction, stroke and ischaemia – reperfusion injury,[5,6,7] thrombosis,[8] as well as small vessel vasculitis.[9]. Neutrophils use a large number of cell surface receptors to sense the inflammatory microenvironment and direct their cellular responses.[17] Those include G-protein-coupled chemokine and other chemoattractant receptors, classical immunoreceptors (e.g. Fc-receptors), adhesion receptors such as selecting and integrins, cytokine receptors, as well as a number of cell surface and intracellular pathogen recognition receptors such as Toll-like receptors, NOD-like receptors, and C-type lectins.[17] All those receptors trigger complex intracellular signalling events leading to various cellular responses including migration through the vessel wall. We will discuss recent studies revealing important contributions of leucocyte (neutrophil) signalling pathways to the generation of the inflammatory microenvironment with a robust indirect role in the leucocyte recruitment process
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