Global strategy for asthma management and prevention

Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm

To get to the site of inflammation, leukocytes must first adhere to and traverse the blood-vessel wall, events that occur in a cascade-like manner. But what are the exact steps in this cascade and what molecules are involved?

Getting to the site of inflammation: the leukocyte adhesion cascade updated

Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Neutrophil recruitment and function in health and inflammation

The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

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Cancer nanomedicine: progress, challenges and opportunities.

Integrins are a family of heterodimeric cell-surface adhesion and signaling molecules each composed of an α and a β subunit. At present 18 α and 8 β subunits have been identified giving rise to 24 distinct integrin molecules. Many members of this family, primarily integrins containing a β1 subunit, act as receptors for extracellular matrix proteins, e.g., α1β1 and α2β1 are key receptors for collagen while α3β1 and α6β1 are key receptors for laminin. The integrin α6β1 (VLA-6, CD49f/CD29) was originally identified on platelets but is now known to be expressed on numerous cell types including epithelial and endothelial cells and is indeed the key leukocyte laminin receptor. Its principal functional role relates to regulation of cell adhesion and motility, and, in line with this, α6β1 interaction with its ligands leads to cellular cytoskeletal rearrangement and polarization. In the context of inflammatory events, the ability of α6β1 to bind vascular laminins has led to much interest in the role of this integrin in regulation of leukocyte migration through the vascular basement membrane (BM). In blood vessels, the BM forms a thin protein sheet that underlies the endothelium and encases the pericytes/smooth muscle cells. Major constituents of this BM are laminins (laminin 8 and laminin 10) and collagen IV, which form two independent networks that are interconnected by molecules such as nidogens (nidogen-1 and nidogen-2) and the large heparan sulfate proteoglycan, perlecan [1]. In contrast to our growing knowledge of the molecules and mechanisms that mediate leukocyte migration through the endothelium [2], less is known about the mechanisms that mediate and regulate leukocyte migration through the vascular BM.

Role of α6β1 integrin in leukocyte adhesion and transmigration

In addition to being useful clinical markers of systemic vasculitis, anti-neutrophil cytoplasm antibodies (ANCA) may play a role in the initiation of vasculitic injury. These autoantibodies can induce neutrophil degranulation, dysregulated neutrophil apoptosis and neutrophil adhesion to endothelium in static cellular systems. This mini-review will place these sentinel findings in the context of more recent studies using the parallel plate flow chamber and novel animal models of ANCA-associated vasculitis (AASV). Rodent models lend themselves well to investigation of leukocyte endothelial interaction using intravital microscopy. In this way, one can study ANCA-induced leukocyte adhesion/transmigration, and microvascular injury in real time. These studies may then be extended to look at the impact of novel therapeutic agents on these processes.

Intravital microscopy in the study of ANCA-associated systemic vasculitis.

A defining feature of an inflammatory reaction is infiltration of neutrophils into tissues, a response that requires breaching of endothelial cells (ECs) that line the lumenal aspect of blood vessels. Dysregulated neutrophil trafficking is a hallmark of pathology, but details of the molecular mechanisms that terminate neutrophil breaching of venular walls remain unclear. In this work, we have identified EC autophagy as a negative regulator of neutrophil diapedesis in acute physiological inflammation. Specifically, in vivo, inflamed venular ECs upregulate autophagy, a response that is selectively localized to EC contacts and temporally aligned with the peak of neutrophil trafficking. Genetic ablation of EC autophagy leads to excessive neutrophil tissue infiltration in multiple inflammatory models and supports enhanced neutrophil transendothelial migration (TEM), while pharmacological induction of autophagy inhibits neutrophil migration. Mechanistically, autophagy machinery regulates the architecture of EC contacts and controls the reorganization and degradation of adhesion molecules, constituting a physiological brake on leukocyte trafficking.

Endothelial cell autophagy keeps neutrophil trafficking under control.

Comparison of the binding characteristics of ANCA from vasculitic patients with ANCA from a novel rat model of systemic vasculitis.

Endothelial cells (ECs) line the inner surface of all vascular walls and as such form a vital barrier between blood and interstitial tissues. Key to this function is the ability of ECs to form cell...

Sussan Nourshargh

Papers

Role of α6β1 integrin in leukocyte adhesion and transmigration

Intravital microscopy in the study of ANCA-associated systemic vasculitis.

Endothelial cell autophagy keeps neutrophil trafficking under control.

Comparison of the binding characteristics of ANCA from vasculitic patients with ANCA from a novel rat model of systemic vasculitis.

JAM-C deficiency primes endothelial cells for a pro-inflammatory state