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.

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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.

TNF-induced signaling in apoptosis.

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

Granulocyte apoptosis is an important mechanism underlyeffect of TNF-a was concentration-dependent (EC50 2.8 ng/ mL), abolished by TNF-a neutralizing antibody, and was not ing the removal of redundant neutrophils from an inflammatory focus. The ability of many proinflammatory agents associated with any change in cell viability or recovery. Of relevance to the inflamed site, the ability of TNF-a to accelerto impede this event suggests that such agents act not only in a priming or secretagogue capacity but also increase neuate apoptosis was lost if neutrophils were primed with 1 mmol/L PAF or aged for 6 hours before TNF-a addition. The trophil longevity by delaying apoptosis. We have examined whether this hypothesis holds true for all neutrophil priming TNFR55-selective TNF-a mutants (E146K, R32W-S86T) induced neutrophil apoptosis but with a potency 14-fold lower agents, in particular tumor necrosis factor-a (TNF-a), which has been variably reported to either induce, delay, or have than wild-type TNF-a. Although the TNFR75-selective mutant (D143F) did not induce apoptosis, blocking antibodies no effect on neutrophil apoptosis. After 20 hours coincubation TNF-a inhibited neutrophil apoptosis; however, more to both receptor subtypes abolished TNF-a–stimulated apoptosis. Hence, TNF-a has the unique ability to induce detailed analysis demonstrated its ability to promote apoptosis in a subpopulation of cells at earlier (2 to 8 hours) apoptosis in human neutrophils via a mechanism where TNFR75 facilitates the dominant TNFR55 death effect. This times. Formyl-Met-Leu-Phe, platelet-activating factor, inositol hexakisphosphate, lipopolysaccharide, leukotriene B4, may be an important mechanism controlling neutrophil longevity and clearance in vivo. and granulocyte-macrophage colony-stimulating factor all inhibited apoptosis at 6 and 20 hours. The early proapoptotic q 1997 by The American Society of Hematology.

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

Mast cells (MCs) are tissue-resident immune cells that mediate IgE-dependent allergic responses. Downstream of FcεRI, an intricate network of receptor-specific signaling pathways and adaptor proteins govern MC function. The 14-3-3 family of serine-threonine phosphorylation-dependent adapter proteins are known to organize intracellular signaling. However, the role of 14-3-3 in IgE-dependent activation remains poorly defined.We sought to determine whether 14-3-3 proteins are required for IgE-dependent MC activation and whether 14-3-3 is a viable target for the treatment of MC-mediated inflammatory diseases.Genetic manipulation of 14-3-3ζ expression in human and mouse MCs was performed and IgE-dependent mediator release assessed. Pharmacologic inhibitors of 14-3-3 and 14-3-3ζ knockout mice were used to assess 14-3-3ζ function in a MC-dependent in vivo passive cutaneous anaphylaxis (PCA) model of allergic inflammation. Expression and function of 14-3-3ζ were assessed in human nasal polyp tissue MCs.IgE-dependent mediator release from human MCs was decreased by 14-3-3ζ knockdown and increased by 14-3-3ζ overexpression. Deletion of the 14-3-3ζ gene decreased IgE-dependent activation of mouse MCs in vitro and PCA responses in vivo. Furthermore, the 14-3-3 inhibitor, RB-11, which impairs dimerization of 14-3-3, inhibited cultured MC and polyp tissue MC activation and signaling downstream of the FcεRI receptor and dose-dependently attenuated PCA responses.IgE/FcεRI-mediated MC activation is positively regulated by 14-3-3ζ. We identify a critical role for this p-Ser/Thr-binding protein in the regulation of MC FcεRI signaling and IgE-dependent immune responses and show that this pathway may be amenable to pharmacologic targeting. 

Angel F. Lopez

Papers

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

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

The IgE receptor of mast cells signals mediator release and inflammation via the adaptor protein 14-3-3ζ.