Molecular and functional changes in neutrophilic granulocytes induced by nicotine: a systematic review and critical evaluation.

Background: Over 1.1 billion people smoke worldwide. The alkaloid nicotine is a prominent and addictive component of tobacco. In addition to tumors and cardiovascular disorders, tobacco consumption is associated with a variety of chronic-inflammatory diseases. Although neutrophilic granulocytes (neutrophils) play a role in the pathogenesis of many of these diseases, the impact of nicotine on neutrophils has not been systematically reviewed so far. Objectives: The aim of this systematic review was to evaluate the direct influence of nicotine on human neutrophil functions, specifically on cell death/damage, apoptosis, chemotaxis, general motility, adhesion molecule expression, eicosanoid synthesis, cytokine/chemokine expression, formation of neutrophil extracellular traps (NETs), phagocytosis, generation of reactive oxygen species (ROS), net antimicrobial activity, and enzyme release. Material and methods: This review was conducted according to the PRISMA guidelines. A literature search was performed in the databases NCBI Pubmed® and Web of Science™ in February 2023. Inclusion criteria comprised English written research articles, showing in vitro studies on the direct impact of nicotine on specified human neutrophil functions. Results: Of the 532 originally identified articles, data from 34 articles were finally compiled after several evaluation steps. The considered studies highly varied in methodological aspects. While at high concentrations (>3 mmol/l) nicotine started to be cytotoxic to neutrophils, concentrations typically achieved in blood of smokers (in the nmol/l range) applied for long exposure times (24-72h) supported the survival of neutrophils. Smoking-relevant nicotine concentrations also increased the chemotaxis of neutrophils towards several chemoattractants, elevated their production of elastase, lipocalin-2, CXCL8, leukotriene B4 and prostaglandin E2, and reduced their integrin expression. Moreover, while nicotine impaired the neutrophil phagocytotic and anti-microbial activity, a range of studies demonstrated increased NET formation. However, conflicting effects were found on ROS generation, selectin expression and release of ß-glucuronidase and myeloperoxidase. Conclusion: Nicotine seems to support the presence in the tissue and the inflammatory and selected tissue-damaging activity of neutrophils and reduces their antimicrobial functions, suggesting a direct contribution of nicotine to the pathogenesis of chronic-inflammatory diseases via influencing the neutrophil biology.

Interleukin-19 Levels Are Increased in Palmoplantar Pustulosis and Reduced following Apremilast Treatment.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.

Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.