Clin Hemorheol Microcirc. 2013 Jan 1;55(4):423-43.

Leukocyte-endothelial interactions within the ocular microcirculation in inflammation and infection.

Al-Banna NA1, Toguri JT2, Kelly ME2, Lehmann Ch3.

  • 1Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 2Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 3Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.



Leukocyte-endothelial interactions within the microvasculature represent a hallmark of inflammation regardless of whether the inflammation results from non-infectious or infectious triggers. In this review, we highlight features of leukocyte recruitment in ocular disease and postulate mechanisms by which the infiltrating cells may lead to the progression of the ocular inflammatory response, including cytokine and chemokine production, T cell or non-T cell responses. Additionally, ex-vivo and in vivo methods used to study the general features of the immune response are discussed, with a specific focus on intravital imaging, which allows real-time non-invasive examination of leukocyte-endothelial interactions in the ocular microvasculature. At the present time there are still significant gaps in our understanding of the process of leukocyte recruitment in vivo in different microvascular beds. Further studies using non-invasive imaging approaches, such as intravital microscopy, provide an opportunity to study dynamic tissue-specific leukocyte-endothelial interactions in vivo and identify novel targets for early intervention in the inflammatory process. This knowledge is essential to the rational use of therapeutics to resolve inflammation in ocular disease.

KEYWORDS: Ocular microcirculation; infection; inflammation; intravital microscopy; leukocyte infiltration; leukocyte-endothelium interaction

PMID: 24113507



Leukocyte-endothelial interactions represent a key component to the response of both infectious and non-infectious inflammation [1]. This review covers these interactions within the eye, how they occur and potential techniques which could aid in further studies. The recruitment of leukocytes are often associated with disease progression, tissue pathology, and tissue damage causing visual impairment or vision loss. Leukocyte-endothelial interactions involve a multi-step process that starts with rolling, whereby circulating leukocytes slow down and roll across the endothelium, firmly adhere to the endothelium and then undergo transendothelial migration [2,3]. Understanding the cellular mechanisms contributing to leukocyte-endothelial interactions in such ocular diseases states such as conjunctivitis (inflammation of the conjunctiva), uveitis/iritis (inflammation of the iris) and chorioretinitis (inflammation of the choroid and retinal layers) is necessary for the advancement of potential therapeutics.

The eye is an ideal system for the non-invasive study of leukocyte recruitment and their interactions with endothelium. Several mediators have been suggested to be involved in the infiltration of immune cells and the pathogenesis of ocular disease. Inflammatory mediators such as cytokines, chemokines and adhesion molecules play a role in the recruitment to areas of inflammation and the interactions leukocytes have with the endothelium at these locations. During ocular inflammation the production of pro-inflammatory cytokines (e.g. TNF-α, IL-1β, IFN-γ, IL-6, IL-8 and IL-12) [4,5,6,7,8] occurs in many ocular diseases. Chemokines such as macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant, and eotaxin have also been shown to increase [8]. There are several receptors and adhesion molecules which also play an integral component to leukocyte-endothelial interactions, such as chemokine receptors, selectins and integrins. This includes the up-regulation of P-selectin glycoprotein, [9] L-selectin and α4-integrin [1]. Adhesion molecules expression of platelet endothelial cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 also increase [10].

A number of studies have modeled inflammation and the infiltration of immune cells in the ocular tissue. These different models focus on specific types ocular inflammation and disease states. It is an important distinction to know that each of these studies have specific immune subsets associated with them. These immune cell subsets include the innate immune cells, like PMNs (neutrophils, eosinophils and basophils/mast cells), monocytes/macrophages, and dendritic cells, as well as adaptive immune cells, such as CD4 T or CD8 T lymphocytes that possess type 1 or type 2 cytokine profiles, or B lymphocytes [11,12]

Non-invasive intravital microscopy (IVM) can be used to study leukocyte recruitment in ocular diseases. IVM provides real-time recordings for leukocyte-endothelial interactions in the ocular microvasculature over a dynamic time period in the same animal [13]. IVM has been shown to detect the increased leukocyte-endothelial cell interaction in the iridal microcirculation and the retinal microcirculation [6]. The most commonly used tools to study leukocyte recruitment have been histological assessment and levels of immune mediators, and thus the cellular mechanisms underlying the process of leukocyte recruitment are not fully elucidated. IVM provides specific knowledge about the kinetics and molecular mechanisms of leukocyte activation in individual vascular beds. At this time, there are extensive gaps of knowledge in the characterization of the mechanisms involved in migration of leukocytes to the ocular tissue. Therefore, it is important for future studies to utilize different animal models of ocular disease, together with dynamic techniques such as IVM, in order to identify tissue-specific mechanisms of leukocyte-endothelial cell interaction. This information is critical for the identification of new drug targets and therapeutic strategies for ocular inflammatory diseases.



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