The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome

Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.

CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases

Inflammatory monocytes are key mediators of acute and chronic inflammation; yet, their functional diversity remains obscure. Single-cell transcriptome analyses of human inflammatory monocytes from COVID-19 and rheumatoid arthritis patients revealed a subset of cells positive for CD127, an IL-7 receptor subunit, and such positivity rendered otherwise inert monocytes responsive to IL-7. Active IL-7 signaling engaged epigenetically coupled, STAT5-coordinated transcriptional programs to restrain inflammatory gene expression, resulting in inverse correlation between CD127 expression and inflammatory phenotypes in a seemingly homogeneous monocyte population. In COVID-19 and rheumatoid arthritis, CD127 marked a subset of monocytes/macrophages that retained hypoinflammatory phenotypes within the highly inflammatory tissue environments. Furthermore, generation of an integrated expression atlas revealed unified features of human inflammatory monocytes across different diseases and different tissues, exemplified by those of the CD127high subset. Overall, we phenotypically and molecularly characterized CD127-imprinted functional heterogeneity of human inflammatory monocytes with direct relevance for inflammatory diseases.

Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme responsible for the hydrolysis of fatty acid ethanolamides (FAEs). However, the role of NAAA in FAEs metabolism and regulation of pain and inflammation remains mostly unknown. Here, we generated NAAA-deficient (NAAA-/-) mice using CRISPR-Cas9 technique, and found that deletion of NAAA increased PEA and AEA levels in bone marrow (BM) and macrophages, and elevated AEA levels in lungs. Unexpectedly, genetic blockade of NAAA caused moderately effective anti-inflammatory effects in lipopolysaccharides (LPS)-induced acute lung injury (ALI), and poor analgesic effects in carrageenan-induced hyperalgesia and sciatic nerve injury (SNI)-induced mechanical allodynia. These data contrasted with acute (single dose) or chronic NAAA inhibition by F96, which produced marked anti-inflammation and analgesia in these models. BM chimera experiments indicated that these phenotypes were associated with the absence of NAAA in non-BM cells, whereas deletion of NAAA in BM or BM-derived cells in rodent models resulted in potent analgesic and anti-inflammatory phenotypes. When combined, current study suggested that genetic blockade of NAAA regulated FAEs metabolism and inflammatory responses in a cell-specifical manner.

Unraveling the Relationship of Asthma and COVID-19

Viral infections are one of the main causes of asthma exacerbations. During the COVID-19 era, concerns regarding the relationship of SARS-CoV2 with asthma have been raised. The concerns are both for COVID severity and asthma exacerbations. Many studies on COVID-19 epidemiology and comorbidities have assessed whether asthma represents a risk factor for SARS-CoV2 infection and/or more severe course of the disease. This review covers the current evidence on the prevalence of asthma in COVID-19 and its association with susceptibility to and severity of SARS-CoV2 infection. It will examine the possible role of underlying asthma severity in COVID-19 related outcomes as well as the molecular mechanisms involved in the co-existence of these entities. The possible role of asthma inflammatory phenotypes will also be evaluated. Finally, the impact of asthma comorbidities and the implications of asthma medication on COVID-19 will be addressed.

TNF plays a crucial role in inflammation by signaling via T cell TNFR2

TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4+ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt+IL-17lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system–infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid–infiltrating CD4+ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.

Peculiarities of response to basic anti-inflammatory therapy of schoolchildren with alternative inflammatory phenotypes of bronchial asthma

Purpose — to evaluate the effectiveness of long-term anti-inflammatory therapy with inhaled glucocorticosteroids in children with alternative inflammatory phenotypes of bronchial asthma (BA) for the development of individualized control treatment. Materials and methods. A comprehensive survey of 94 school-age children with BA was conducted. According to the results of cytological examination of sputum, 2 clinical observation groups were formed. The first group of patients was formed by 38 patients with non3eosinophilic (neutrophilic) nature of the inflammatory process of the bronchi (mean age — 11.1±2.9 years, the proportion of boys — 52.6±8.1%), and the second group — 56 children with eosinophilic type of airway inflammation (3% or more of eosinophilic granulocytes in sputum), ie eosinophilic asthma phenotype (mean age — 12.2±3.2 (P>0.05) years, the proportion of boys — 67.9±6.2%, P>0.05). According to the main characteristics of the observation group could be compared. All patients underwent a comprehensive clinical and paraclinical (spirographic) examination. Scoring control of BA symptoms was performed using a questionnaire at the beginning and at the end of the course of anti-inflammatory basic therapy. The questionnaire included the clinical signs of BA reflected in the scores, which were evaluated by patients and their parents, as well as the scale of instrumental studies according to the spirographic examination of patients. Results. The paper shows that the best effect of long-term courses of basic therapy with inhaled glucocorticosteroids (ICS) was observed in patients with eosinophilic airway inflammation. Thus, the share of patients with a relatively satisfactory level of clinical control of the disease and with close to normal spirographic indicators was in group II: before the course of treatment with inhaled corticosteroids 25.0% and 31.9%, and after treatment — 81.3% (P<0,01) and 69.0% (P<0.01), respectively. Thus, an increase of 69.3% in relative risk (IRR) and 56.3% in absolute risk (IAR) of BA control reflected a pronounced control effect of inhaled corticosteroids in the eosinophilic nature of airway inflammation. The minimum number of patients needed to treat (NNT) in order to obtain at least one positive result was 2. At the same time, in patients with neutrophilic inflammatory process, the proportion of patients with a relatively satisfactory level of clinical and paraclinical (according to spirography) disease control was: before the appointment of ICS — 30.8% and 30.8%, and after treatment — 50% (PFisher's exact test>0.05) and 76.9% (PFisher's exact test<0.01), respectively. This persistence of clinical manifestations of the disease indicated an insufficient level of control of non3eosinophilic BA in the treatment of inhaled corticosteroids and questioned the feasibility of monotherapy with this group of neutrophilic bronchitis. The insufficient effect of anti3inflammatory therapy with inhaled corticosteroids was evidenced by the fact that IRR of satisfactory level of clinical control was 38.4%, IAR — 19.2%, and NNT — 6 patients. Conclusions. In patients with the eosinophilic phenotype of BA, the use of long courses of inhaled glucocorticosteroids led to an increased chance of achieving disease control, while the chances of improving of the pulmonary function tests were also observed in the neutrophilic phenotype of the disease. The research was carried out in accordance with the principles of the Helsinki declaration. The study protocol was approved by the Local ethics committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: bronchial asthma, children, basic anti-inflammatory therapy.

Distribution of inflammatory phenotypes among patients with asthma in Jilin Province, China: a cross-sectional study

Background The inflammatory phenotypes of asthma predict the treatment response and prognosis. The phenotype distributions differ depending on the geographical region. This study aimed to assess the distribution of different inflammatory phenotypes among asthma patients in Jilin Province, China. Methods A total of 255 patients with asthma were recruited from Jilin Province, China for this cross-sectional study. Each patient underwent sputum induction following clinical assessment and peripheral blood collection. Inflammatory phenotypes were classified according to the inflammatory cell counts in the sputum. Results Paucigranulocytic asthma (PGA) was the most common inflammatory phenotype (52.2%), followed by eosinophilic asthma (EA, 38.3%), mixed granulocytic asthma (MGA, 5.2%), and neutrophilic asthma (NA, 4.3%). NA was more common among patients over 45 years old and those who were treated with higher doses of inhaled corticosteroids (ICS), but was less common following antibiotics treatment (p < 0.05). The proportion of patients with EA decreased as the ICS treatment dose and time increased (p = 0.038). Patients with uncontrolled asthma had higher numbers of sputum eosinophils and neutrophils (p < 0.05). Patients with severe asthma had a higher percentage of sputum neutrophils (p < 0.05). A greater proportion of patients with NA had severe asthma (60%) compared to those with EA (18.2%) (p = 0.016). Conclusions The most common asthma inflammatory cell phenotype in Jilin Province, China is PGA, followed by EA, MGA, and NA. The low prevalence of NA in Jilin Province compared to other countries and also other regions in China might be due to excessive antibiotic use and irregular ICS treatment in this region.