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  • Review Article
  • Published:

Intravascular immunity: the host–pathogen encounter in blood vessels

Nature Reviews Immunology volume 9, pages 364–375 (2009)Cite this article

Key Points

  • Our understanding of how the immune system deals with invading bacterial pathogens has been greatly improved by recent in vivo imaging studies. These studies commonly use novel imaging modalities such as spinning disk and multi-photon confocal microscopy, in combination with strains of mice that are genetically engineered to express fluorescent proteins under the control of cell subset-specific promoters.

  • These studies have revealed that intravascular migration is necessary for efficient transendothelial migration of neutrophils and monocytes. Also, monocytes (in the dermal vasculature and other sites) and invariant natural killer T (iNKT) cells (specifically in the hepatic microvasculature) undergo intravascular migration or crawling, potentially as a form of constitutive immune surveillance of the microvasculature.

  • Endothelial cells also contribute to innate immune responses to bacterial pathogens. They express the cellular machinery necessary for responses to bacteria (such as Toll-like receptors, MD2 and signalling adaptor molecules), but also potentially contribute to the inappropriate immune response in sepsis.

  • Neutrophils, which use neutrophil extracellular traps (NETs) consisting of chromatin and proteases to trap and kill bacteria, undergo platelet-dependent activation in the vasculature under conditions of high bacteraemia. This results in NET formation within the vasculature; under such circumstances, NETs can act as an additional form of intravascular immunity.

  • Bacteria have evolved a wide range of approaches for evading and/or combating the immune system. These include hiding from immune recognition by adhering to and invading endothelial cells, and inhibiting complement activation.

  • Many bacterial products actively antagonize leukocyte recruitment. These include lipopolysaccharide, which promotes leukocyte retention away from the site of infection and inhibits leukocyte migration, and Staphylococcus aureus proteins such as chemotaxis inhibitory protein of S. aureus and the extracellular adherence protein, which directly inhibit molecules that are involved in leukocyte adhesion and migration.

Abstract

The immune system provides an essential defence against invading pathogens. However, bacteria have evolved numerous strategies to overcome this defence, many of which facilitate systemic dissemination of the pathogen. Nevertheless, the host has evolved many mechanisms to detect and protect against pathogens in the vasculature. Recent studies using new imaging approaches and new mouse models are revealing previously unappreciated functions of this intravascular aspect of the immune system. In this Review, we summarize recent work in this field, highlighting in vivo imaging studies that examine the behaviour of both the immune system and bacteria in the highly dynamic microvasculature.

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Figure 1: Diverse microcirculatory sites for leukocyte recruitment.
Figure 2: Cellular and molecular interactions for immune surveillance and recruitment in the dermal and hepatic vasculature.
Figure 3: In vivo imaging reveals cell populations in hepatic vasculature.
Figure 4: Neutrophil extracellular traps: an additional antibacterial weapon.
Figure 5: Adhesion and translocation of Borrelia burgdorferi in the vasculature.
Figure 6: Bacterial distraction mechanisms in the vasculature.

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Acknowledgements

This work is supported by a programme grant (334067) from the National Health and Medical Research Council of Australia. M.J.H. is a National Health and Medical Research Council senior research fellow.

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Authors and Affiliations

  1. Monash University Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, 3168, Victoria, Australia

    Michael J. Hickey

  2. Snyder Institute of Infection, Immunity and Inflammation, University of Calgary Health Sciences Centre, Calgary, T2N 4N1, Alberta, Canada

    Paul Kubes

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Glossary

Intravital microscopy study

An examination of biological processes, such as leukocyte–endothelial cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, which can be exteriorized and mounted for microscopic observation.

High endothelial venule

(HEV). A specialized venule that is found in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Shear stress

The force exerted by the flowing blood (dynes) on each unit of area of endothelial surface (cm2); measured in dynes per cm2.

Kupffer cell

A large, specialized ramified macrophage that lines the sinusoidal vessels of the liver. Kupffer cells regulate local immune responses and remove microbial particles, endotoxins and other noxious substances that penetrate the portal venous system.

Spinning disk confocal microscopy

Form of confocal microscopy in which confocality is achieved using a spinning disk with numerous pinholes, replacing the more conventional laser scanning process that is used in many confocal microscopes. The main advantage of this form of confocal microscopy is the rapid rate of image capture (up to ∼15 frames per second), which enables examination of rapidly motile cells and bacteria in the vasculature.

C3 receptor

A receptor that mediates responses to the complement components C3 and C3a. Four C3 fragment receptors have been identified: CR1 (CD35), CR2 (CD21), CR3 (CD11b–CD18) and CR4 (CD11c–CD18). However, none of these receptors has been described to be functional on Kupffer cells.

Contact sensitization

The inflammatory immune reactions that occur in the skin after the administration of a sensitizing antigen. These reactions occur after the second and subsequent exposures to a particular sensitizing antigen and involve the recruitment and responses of effector T cells.

Ito cell

A type of pericyte that is found in the space of Disse and is the main reservoir of retinol in the liver.

Space of Disse

The space between the sinusoidal endothelial cells and hepatocytes in which Ito cells are found. Given the discontinuous nature of the sinusoidal endothelium, this space is filled with blood plasma. Hepatocytes extend microvilli into the space of Disse, thereby increasing their surface area for metabolite exchange.

Fenestrated endothelium

Large holes (fenestrations) of the endothelium of the hepatic sinusoids, which allow plasma in the sinusoids to freely access the space of Disse.

Toll-like receptor

(TLR). A receptor belonging to a family that recognizes conserved products that are unique to microorganisms (such as lipopolysaccharide), which are known as pathogen-associated molecular patterns. TLR-mediated events signal to the host that a microbial pathogen is present.

Caecal ligation and puncture

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured, thereby forming a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

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Hickey, M., Kubes, P. Intravascular immunity: the host–pathogen encounter in blood vessels. Nat Rev Immunol 9, 364–375 (2009). https://doi.org/10.1038/nri2532

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