(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

/pdf/modulating-innate-and-adaptive-immunity-by-r-roscovitine-4p801w2q1i.pdf

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.

/pdf/inflammatory-responses-and-inflammation-associated-diseases-1vf5a1j4st.pdf

Inflammatory responses and inflammation-associated diseases in organs

Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

/pdf/neutrophils-in-the-activation-and-regulation-of-innate-and-2ccbalvc3n.pdf

Neutrophils in the activation and regulation of innate and adaptive immunity

Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.

Vitamin C and Immune Function

A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.

Macrophage death and defective inflammation resolution in atherosclerosis.

Neutrophils are the most abundant cell type involved in the innate immune response. They are rapidly recruited to sites of injury or infection where they engulf and kill invading microorganisms. Neutrophil apoptosis, the process of programmed cell death that prevents the release of neutrophil histotoxic contents, is tightly regulated and limits the destructive capacity of neutrophil products to surrounding tissue. The subsequent recognition and phagocytosis of apoptotic cells by phagocytic cells such as macrophages is central to the successful resolution of an inflammatory response and it is increasingly apparent that the dying neutrophil itself exerts an anti-inflammatory effect through modulation of surrounding cell responses, particularly macrophage inflammatory cytokine release. Apoptosis may be delayed, induced or enhanced by micro-organisms dependent on their immune evasion strategies and the health of the host they encounter. There is now an established field of research aimed at understanding the regulation of apoptosis and its potential as a target for therapeutic intervention in inflammatory and infective diseases. This review focuses on the physiological regulation of neutrophil apoptosis with respect to the innate immune system and highlights recent advances in mechanistic understanding of apoptotic pathways and their therapeutic manipulation in appropriate and excessive innate immune responses.

/pdf/neutrophil-apoptosis-relevance-to-the-innate-immune-response-1yhncbb5af.pdf

Neutrophil Apoptosis: Relevance to the Innate Immune Response and Inflammatory Disease

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(08)00072-2.pdf

Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation

The inflammatory process is a complex series of tightly controlled cellular and biochemical events initiated by the immune system, which has evolved to eliminate or contain infectious agents and to repair damaged tissue. Apoptosis is essential for the clearance of potentially injurious inflammatory cells, such as neutrophils, eosinophils, and basophils, and the subsequent efficient resolution of inflammation. In this review, we aim to cover key features of the granulocyte life-cycle ranging from their differentiation within the bone marrow to their maturation and ultimate clearance, with a focus on granulocyte apoptosis and macrophage efferocytosis. We further aim to discuss current and emerging models of inflammation and suggest novel ways of terminating or resolving deleterious inflammatory responses with a specific view to the translation of these strategies into fully realized, pro-resolution therapies.

Targeting granulocyte apoptosis: mechanisms, models, and therapies

Relevance of granulocyte apoptosis to resolution of inflammation at the respiratory mucosa.

Introduction and Objectives Terminally-differentiated neutrophils are short-lived but key effector cells of the innate immune response and play a prominent role in the pathogenesis and propagation of many inflammatory diseases including interstitial lung disease. BAL neutrophilia has been correlated with poor outcome in idiopathic pulmonary fibrosis (IPF) and neutrophils are the dominant cell type in acute exacerbations of IPF as well as in diffuse alveolar damage. Non-specific cyclin-dependent kinase inhibitor drugs have previously been shown to resolve neutrophil-dominant inflammation in the murine bleomycin lung injury model an established model of IPF. Here we elucidate the mechanism by which CDK inhibitor drugs mediate neutrophil apoptosis and hence promote resolution of inflammation. Methods We isolated peripheral blood neutrophils from healthy human donors and performed a variety of experiments including microarray, confocal microscopy and apoptosis assays (flow cytometry, fluorometric assay, DNA ladders and mitochondrial integrity assay and western blotting) to show that specific effects on neutrophil transcriptional capacity are responsible for CDK-inhibitor driven neutrophil apoptosis. Finally we show that specific CDK inhibitors drive resolution of neutrophil-dominant inflammation in the murine bleomycin lung injury model (Histology, BAL analysis). Results CDK inhibitors drive neutrophil apoptosis. Neutrophil apoptosis is dependent on a critical balance of pro- and anti-apoptotic proteins. Functional transcriptional machinery is present in human peripheral blood neutrophils. CDKs are present in neutrophils and their activity is both demonstrated and modulated with the use of specific CDK inhibitors. Specific CDK inhibition is a successful strategy for the resolution of murine bleomycin lung injury. Conclusion We highlight a novel mechanism that controls both neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established neutrophil-dominant inflammation.

https://thorax.bmj.com/content/thoraxjnl/66/Suppl_4/A104.2.full.pdf

Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation

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