Pathophysiology 12 (2005) 191–202 Neutrophil gene expression in rheumatoid arthritis Andrew Cross a , Denise Bakstad a , John C. Allen a , Luke Thomas a , Robert J. Moots b , Steven W. Edwards a,∗ a School of Biological Sciences, Biosciences Building, University of Liverpool, Liverpool L69 7ZB, UK b Department of Medicine, University of Liverpool, Liverpool L69 3BX, UK Abstract There is now a growing awareness that infiltrating neutrophils play an important role in the molecular pathology of rheumatoid arthritis. In part, this arises from the fact that neutrophils have potent cytotoxic activity, but additionally from the fact that inflammatory neutrophils can generate a number of cytokines and chemokines that can have a direct influence on the progress of an inflammatory episode. Furthermore, the molecular properties of inflammatory neutrophils are quite different from those normally found in the circulation. For example, inflammatory neutrophils, but not blood neutrophils, can express cell surface receptors (such as MHC Class II molecules and FcRI) that dramatically alter the way in which these cells can interact with ligands to modulate immune function. Cytokine/chemokine expression and surface expression of these novel cell surface receptors is dependent upon the neutrophil responding to local environmental factors to selectively up-regulate the expression of key cellular components via signalling pathways coupled to transcriptional activation. However, major changes in the expression levels of some proteins are also regulated by post-translational modifications that alter rates of proteolysis, and hence changes in the steady-state levels of these molecules. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Neutrophil gene expression; Rheumatoid arthritis; Cytokines; Apoptosis 1. Neutrophils and rheumatoid arthritis The neutrophil is the most abundant of all cells in the joints of patients with active rheumatoid arthritis [1], and yet is a relatively understudied cell in this disease. This seems rather surprising in view of the fact that of all immune cells, neu- trophils possess tremendous cytotoxic potential and hence the greatest capacity to inflict tissue damage [2]. The pri- mary function of neutrophils is to recognise, phagocytose and kill invading microorganisms to protect the host from infections and so they are highly specialised cells with potent cytotoxic mechanisms and processes [3]. These include the ability to generate large quantities of reactive oxygen species (including O 2 - ,H 2 O 2 , HOCl, 1 O 2 and • OH) and a vari- ety of proteases and other permeability-inducing factors, such as cathepsin G, elastase, collagenase and protease 3 [2,4,5]. The ability of neutrophils to inflict tissue damage during inflammation arises from their capacity to secrete, ∗ Corresponding author. Tel.: +44 151 795 4413; fax: +44 151 795 4414. E-mail address: S.W.Edwards@liv.ac.uk (S.W. Edwards). in large quantities, the components of their anti-microbial arsenal into the extracellular milieu. Whilst the role for reac- tive oxygen species in direct microbial killing has recently been questioned [6,7], released reactive oxidants can result in oxidative damage to biological molecules either directly or indirectly via the activation of latent proteases, such as collagenase and gelatinase if they overcome the anti-oxidant capacity of tissues. Similarly, released proteases can damage host tissues if they are able to overcome the protective anti- proteinase capacity of tissues and fluids. Reactive oxidants and proteinases may thus act co-operatively to cause damage to tissues. Neutrophils are abundant in the synovial fluid of patients with active rheumatoid arthritis and a typical knee joint may contain in excess of 50 mL of synovial fluid containing 2 × 10 9 cells, 90% of which may be neutrophils. Neutrophils are presumed to be largely absent from joint tissues, but they have been found in cartilage and in the pannus:cartilage interface, the site of active joint erosion, particularly in early stages of the disease [8]. Neutrophils are attracted into dis- eased joints by the chemoattractants commonly detected in 0928-4680/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pathophys.2005.07.006