In inflammatory conditions such as RA, the neutrophil has tended to be dismissed as a short-lived, terminally differentiated, irrelevant bystander cell. However, this is clearly not the case. A better understanding of the complex heterogeneous pathways and processes that constitute RA, in parallel with a more sophisticated knowledge of neutrophil biology has identified many potential roles for these cells in the persistence of inflammation and progression of joint damage, which should not be underestimated. Not only are neutrophils found in high numbers within the rheumatoid joint, both in synovial tissue and in joint fluid, they have a huge potential to directly inflict damage to tissue, bone and cartilage via the secretion of proteases and toxic oxygen metabolites, as well as driving inflammation through antigen presentation and secretion of cytokines, chemokines, prostaglandins and leucotrienes. Drugs already used to treat RA down-regulate many neutrophil functions, including migration to the joint, degranulation and production of inflammatory mediators, and these cells should be considered as important targets for the development of new therapies in the future.

/pdf/neutrophil-function-in-inflammation-and-inflammatory-3d4j7ltn91.pdf

Neutrophil function in inflammation and inflammatory diseases

TNF receptor subtype signalling: differences and cellular consequences.

Elucidation of the poorly understood mechanisms by which acute inflammation normally resolves is likely to provide new insights into the pathogenesis of persistent inflammatory states that characterize inflammatory disease and generate new therapeutic targets. We have concentrated on the mechanisms by which granulocytes and their histotoxic contents are cleared from inflamed sites during resolution. Although it had been assumed that extravasated neutrophils disintegrated (undergo necrosis) in situ, we have demonstrated an alternative fate, whereby the cell undergoes apoptosis, a process that has different implications for the control of inflammation. During apoptosis the neutrophil retains its granule contents and loses the ability to secrete them in response to secretagogues. In contrast to necrotic neutrophils, apoptotic neutrophils are ingested by inflammatory macrophages employing novel phagocytic recognition mechanisms that fail to provoke a macrophage proinflammatory response. These recognition mechanisms can be modulated by a number of environmental factors and may represent a pivotal point in the control of inflammation, since if apoptotic granulocytes are not rapidly cleared they undergo secondary necrosis with all the detrimental consequences entailed. The apoptotic clearance pathway is also available to eosinophil granulocytes, but our work suggests that the internal controls may be different from those in neutrophils. For example, corticosteroids delay neutrophil apoptosis but greatly accelerate eosinophil apoptosis, in what may represent a previously unsuspected beneficial mechanism of steroid action in allergic diseases such as bronchial asthma. Furthermore, such differences may lead to novel therapies based on the specific induction of eosinophil apoptosis. Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.160.supplement_1.4

Granulocyte apoptosis and its role in the resolution and control of lung inflammation.

Molecular control of neutrophil apoptosis.

Out of the almost 17 members of the TNF superfamily, TNF is probably the most potent inducer of apoptosis. TNF activates both cell-survival and cell-death mechanisms simultaneously. Activation of NF-kB-dependent genes regulates the survival and proliferative effects pf TNF, whereas activation of caspases regulates the apoptotic effects. TNF-induced apoptosis is mediated primarily through the activation of type I receptors, the death domain of which recruits more than a dozen different signaling proteins, which together are considered part of an apoptotic cascade. This cascade does not, however, account for the role of reactive oxygen intermediates, ceramide, phospholipases, and serine proteases which are also inplicated in TNF-induced apoptosis. This cascade also does not explain how type II TNF receptors which lack the death domain, induce apoptosis. Nevertheless, this review of apoptosis signaling will be limited to those proteins that makeup the cascade.

Jeffrey A.J. Barbara

Papers

Regulation of Neutrophil Apoptosis by Tumor Necrosis Factor-α: Requirement for TNFR55 and TNFR75 for Induction of Apoptosis In Vitro