Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell \"variants\" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Advanced cystic fibrosis (CF) lung disease is commonly characterized by a chronic Pseudomonas aeruginosa infection and destructive inflammation caused by neutrophils. However, the lack of convincing evidence from most informative biomarkers of severe lung dysfunction (SLD-CF) has hampered the formulation of a conclusive, targeted diagnosis of CF. The aim of this study was to determine whether SLD-CF is related to the high concentration of sputum inflammatory mediators and the presence of biofilm-forming bacterial strains. Forty-one patients with advanced CF lung disease were studied. The severity of pulmonary dysfunction was defined by forced expiratory volume in 1 second (FEV1) < 40%. C-reactive protein (CRP) and NLR (neutrophil-lymphocyte ratio) were examined as representative blood-based markers of inflammation. Expectorated sputum was collected and analysed for cytokines and neutrophil-derived defence proteins. Isolated sputum bacteria were identified and their biofilm-forming capacity was determined. There was no association between FEV1% and total number of sputum bacteria. However, in the high biofilm-forming group the median FEV1 was < 40%. Importantly, high density of sputum bacteria was associated with increased concentrations of neutrophil elastase and interleukin (IL)-8 and low concentrations of IL-6 and IL-10. The low concentration of sputum IL-6 is unique for CF and distinct from that observed in other chronic pulmonary inflammatory diseases. These findings strongly suggest that expectorated sputum is an informative source of pulmonary biomarkers representative for advanced CF and may replace more invasive bronchoalveolar lavage analysis to monitor the disease. We recommend to use of the following inflammatory biomarkers: blood CRP, NLR and sputum elastase, IL-6, IL-8 and IL-10.

OBJECTIVE: The neutrophil to lymphocyte ratio (NLR) is a non-specific, easy-to-obtain marker of inflammation associated with morbidity and mortality in systemic, psychiatric, and age-related inflammatory conditions. Given the growing trend of substance use disorder (SUD) in older adults, and the relationship between inflammation and SUD elevated NLR may serve as a useful inflammatory biomarker of the combined burden of aging and SUD. The present study focused on cocaine use disorder (CUD) to examine if cocaine adds further inflammatory burden among older adults, by comparing NLR values between older adults with CUD and a non-cocaine using, aged-matched, nationally representative sample.
METHODS: The dataset included 107 (86% male) participants (aged 50-65 years) with cocaine use disorder. NLR was derived from complete blood count tests by dividing the absolute value of peripheral neutrophil concentration by lymphocyte concentration. For comparison, we extracted data from age-matched adults without CUD using the National Health and Nutrition Examination Survey. Individuals with immunocompromising conditions were excluded (e.g., rheumatoid arthritis and sexually transmitted infections such as HIV). A doubly-robust inverse probability-weighted regression adjustment (IPWRA) propensity score method was used to estimate group differences on NLR while controlling for potential confounding variables (age, gender, race, income, nicotine, marijuana and alcohol use).
RESULTS: The IPWRA model revealed that the CUD sample had significantly elevated NLR in comparison to non-cocaine users, with a moderate effect size (β weight = 0.67).
CONCLUSIONS: Although non-specific, NLR represents a readily obtainable inflammatory marker for SUD research. CUD may add further inflammatory burden to aging cocaine users.

Immunosenescence is a remodeling of the immune system, caused by aging, with changes in the function of neutrophils, lymphocytes, and Treg cells.
This study aimed to evaluate the expression of molecules CD11b, CD16 and CD64 (neutrophils), CD154 (T lymphocytes), CD40 (B lymphocytes), and to quantitatively analyze the Treg cell subpopulation.
49 elderlies (≥60 years) and 49 adults (≤35 years) were studied. Flow cytometry was used to analyze the expression of surface molecules and the subpopulation of Treg cells, and the results between the groups were compared statistically by the t-test.
There was a decreased significance in the expression of CD11b and CD40 in the elderly.
Decreased CD11b expression can result in susceptibility to infectious diseases, and impairment of phagocytic capacity. Decreased CD40 expression can result in a decline in B lymphocyte activation. The other molecule studied presented alterations not significant, but compatible with the immunological changes in aging.

Cathelicidins form one of the major families of antimicrobial peptides and have been identified in many vertebrates, including humans. LL-37, the only human member of the cathelicidin family, is detected in most sites of the human body that is normally exposed to microbes, including the epithelial lining of the skin, gastrointestinal tract, genitourinary tract and lungs. This peptide is also expressed by a variety of epithelial cells and immune cells, such as neutrophils, monocytes and mast cells. LL-37 has emerged as a key component of innate immunity due to its direct antimicrobial activity against a broad spectrum of invading pathogens. It also exhibits diverse immunomodulatory functions by activating both pro- and anti-inflammatory mediators; inducing cell migration, proliferation and differentiation; and regulating apoptosis of epithelial cells and neutrophils. Given that the phenotypic and functional properties of immune compartments are different and significantly impacted by the anatomical sites, tissue-specific factors of host origin and microbial communities play important roles in the regulation of LL-37. This review summarizes the expression and biological functions of LL-37 and discusses its significant roles in the innate immune system based on its anatomical distribution.

Metformin, a widely prescribed blood glucose normalizing antidiabetic drug, is now beginning to receive increasing attention due to its anti-inflammatory properties.
To provide a critical and comprehensive review of the available literature describing the effects of metformin on the immune system and on auto-inflammatory diseases.
Based on the available scientific literature, metformin suppresses immune responses mainly through its direct effect on the cellular functions of various immune cell types by induction of AMPK and subsequent inhibition of mTORC1, and by inhibition of mitochondrial ROS production. Among key immune events, this results in inhibited monocyte to macrophage differentiation and restrained inflammatory capacity of activated macrophages. In addition, metformin treatment increases differentiation of T cells into both regulatory and memory T cells, as well as decreasing the capacity of neutrophils to commence in NETosis. Due to its inhibitory effect on the proinflammatory phenotype of immune cells, metformin seems to reduce auto-immune disease burden not only in several animal models, but has also shown beneficial results in some human trials.
Based on its immunomodulatory properties and high tolerability as a drug, metformin is an interesting add-on drug for future trials in treatment of immune mediated inflammatory diseases.

Understanding the mechanisms by which Entamoeba histolytica drives gut inflammation is critical for the development of improved preventive and therapeutic strategies. E. histolytica encodes a homolog of the human cytokine macrophage migration inhibitory factor (MIF). Here, we investigated the role of E. histolytica MIF (EhMIF) during infection. We found that the concentration of fecal EhMIF correlated with the level of intestinal inflammation in persons with intestinal amebiasis. Mice treated with antibodies that specifically block EhMIF had reduced chemokine expression and neutrophil infiltration in the mucosa. In addition to antibody-mediated neutralization, we used a genetic approach to test the effect of EhMIF on mucosal inflammation. Mice infected with parasites overexpressing EhMIF had increased chemokine expression, neutrophil influx, and mucosal damage. Together, these results uncover a specific parasite protein that increases mucosal inflammation, expands our knowledge of host-parasite interaction during amebic colitis, and highlights a potential immunomodulatory target.

Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication.

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is a key mediator of neutrophil infiltration and is profibrotic in the liver, lung, and infarcted heart, but its roles in angiotensin II (Ang II)-induced hypertension and cardiac remodeling have not been fully determined. Thus, we sought to investigate the causal relation of G-CSF to neutrophil recruitment and cardiac fibrosis in C57BL/6J mice.
METHODS: Hypertension and cardiac fibrosis were induced in wild-type (WT) mice receiving continuous infusion of Ang II (1,500ng/kg/min). After 7 days, heart sections were stained with hematoxylin and eosin, Masson\'s trichrome, and immunohistochemistry. The mRNA expression of cytokines was detected by real-time polymerase chain reaction analysis. The protein levels were measured by Western blot analysis.
RESULTS: After Ang II infusion, myocardial G-CSF expression was significantly elevated in the hearts. Moreover, WT mice exhibited increased blood pressure, marked neutrophil accumulation, proinflammatory cytokine expression, reactive oxygen species production, and cardiac fibrosis after 7 days of Ang II infusion. However, administration of anti-G-CSF neutralizing antibody, but not with control immunoglobulin G, significantly attenuated these effects. In addition, neutralizing G-CSF antibody reversed Ang II-induced activation of ERK1/2, STAT3, and AKT signaling pathways in the hearts.
CONCLUSIONS: This study demonstrates that G-CSF plays a critical role in hypertension and cardiac fibrosis and targeting this cytokine may be a novel therapeutic strategy to ameliorate hypertensive heart disease.