Christie (Canada)

Specific congenic mice derived from inbred C3H/HeJ mice, which present early onset pneumonitis, and C57BL/6J mice manifesting later onset pneumonitis with pulmonary fibrosis, vary in time to respiratory distress from these responses following whole thorax irradiation. Herein, to investigate a potential adaptive immunity contribution to lung disease in this model, we used flow cytometry to enumerate the pulmonary lymphocytes of C3H/HeJ, C57BL/6J and three lines of sub/congenic mice, at respiratory distress from 18Gy whole thorax irradiation and in strain matched controls. CD4 + lymphocyte % of C3H/HeJ mice exceeded that of C57BL/6J mice at both radiation-induced respiratory distress and in unirradiated controls (P < 0.04) and pulmonary CD4+% was reduced, at distress relative to control levels, in fibrosis responding strains. CD8 + lymphocyte % was reduced in distressed mice, compared to controls, for 8 of 10 comparisons by strain and sex including those of both pneumonitis and pneumonitis with fibrosis responses. γδ + lymphocyte % was largely unchanged at distress from control levels. Time to radiation-induced respiratory distress, and strain fibrosis score, were each negatively correlated with pulmonary CD4+%, and with the CD4/CD8 ratio, measured in distressed mice (r<-0.76; P < 0.01) or in unirradiated controls (r<-0.75; P < 0.02). Inclusion of the lymphocyte profile of unirradiated mice of a separate C3H/HeJ and C57BL6/J-derived congenic line, named Radpf1 and known to be spared radiation-induced lung disease, yielded a pulmonary CD4+% correlation with time to respiratory distress of (r = 0.16, P = 0.76) and of (r=-0.83; P = 0.04) for strain fibrosis score. Pulmonary lymphocyte profiling revealed strain-dependent %CD4 + lymphocytes, measured in mice manifesting radiation-induced respiratory distress or in untreated controls, to correlate with fibrotic lung disease in this mouse model.

Severe COVID-19 is associated with neutrophilic inflammation and immunothrombosis. Several members of the IL-17 cytokine family have been associated with neutrophilic inflammation and activation of the endothelium. Therefore, we investigated whether these cytokines were associated with COVID-19. We investigated the association between COVID-19 and circulating plasma levels of IL-17 cytokine family members in participants to the Biobanque québécoise de la COVID-19 (BQC19), a prospective observational cohort and an independent cohort from Western University (London, Ontario). We measured the in vitro impact of IL-17F on intercellular adhesion molecule 1 (ICAM-1) cell surface expression and neutrophil adhesion on endothelial cells in culture. The contribution of two Mitogen Activated Protein Kinase (MAPK) pathways was determined using small molecule inhibitors PD184352 (a MKK1/MKK2 inhibitor) and BIRB0796 (a p38 MAPK inhibitor). We found increased IL-17D and IL-17F plasma levels when comparing SARS-CoV-2-positive vs negative hospitalized participants. Moreover, increased plasma levels of IL-17D, IL-17E and IL-17F were noted when comparing severe versus mild COVID-19. IL-17F, but not IL-17A, was significantly elevated in people with COVID-19 compared to healthy controls and with more severe disease. In vitro work on endothelial cells treated with IL-17F for 24h showed an increase cell surface expression of ICAM-1 accompanied by neutrophil adhesion. The introduction of two MAPK inhibitors significantly reduced the binding of neutrophils while also reducing ICAM-1 expression at the surface level of endothelial cells, but not its intracellular expression. Overall, these results have identified an association between two cytokines of the IL-17 family (IL-17D and IL-17F) with COVID-19 and disease severity. Considering that IL-17F stimulation promotes neutrophil adhesion to the endothelium in a MAPK-dependent manner, it is attractive to speculate that this pathway may contribute to pathogenic immunothrombosis in concert with other molecular effectors.

The 32.1 MbCnes2chromosome 17 interval was shown to confer resistance to progressiveCryptococcus deneoformans52D infection. To refine the location ofCnes2host resistance genes, a subcongenic mouse strain (B6.CBA-Cnes2b) that contains 8.7 Mb from the telomeric region ofCnes2was created. At 28 days postinfection B6.CBA-Cnes2bmice had a lower lung fungal burden, increased lung injury, as well as mortality compared to C57BL/6N. B6.CBA-Cnes2bmice had increased pulmonary production of pro-inflammatory mediators, chemokines and Th1-type cytokines as well as increased recruitment of monocytes and neutrophils to the lungs.Cnes2balso regulated several elements of the host response toC. deneoformans52D infection in a sex-dependent manner. Specifically, male B6.CBA-Cnes2bmice had a lower lung fungal burden, increased brain injury and mortality relative to females. Taken together these findings demonstrate thatCnes2bregulates host inflammation in a manner that controls fungal burden and increases tissue damage. Precise identification of the genes encoded byCnes2bcould reveal key mechanisms of cryptococcal host resistance and immune reconstitution or postinfectious inflammatory syndromes.

BackgroundThe family of Suppressor of Cytokine Signaling (SOCS) acts as a controller of the duration and intensity of cytokine function by negatively regulating the JAK-STAT signaling pathway. SOCS’ role in inflammatory diseases in animal models is well demonstrated. However, its role in the development of human disease is still under investigation. SOCS3 plays an important role in tumor development where its downregulation has been implicated in the pathogenesis of various solid tumors such as triple-negative breast cancer.AimThe aim of this work was to study (1) the expression of SOCS3 in smokers’ lungs and its relation to the degree of inflammation and (2) SOCS3 regulation by microRNA (miRNA) in alveolar-macrophage (AM)-derived extracellular vesicles (EVs) in bronchoalveolar lavage (BAL).MethodsGroup A: 35 smokers’ [19 with COPD (SC) and 16 without COPD (S)] and 9 nonsmokers (NS); SOCS3, TNFα in AM, and CD8+ T cells were quantified by immunohistochemistry, in lung tissue. Group B: additional 9 SC, 11 S, and 5 NS; AM-EVs expressing SOCS3 (CD14+SOCS3+) and SOCS3 suppressors miRNA-19a-3p and 221-3p in EVs were quantified by flow cytometry and PCR, in BAL.ResultsThe percentage of SOCS3+ AM was higher in SC [68 (6.6–99)%] and S [48 (8–100)%] than in NS [9.6 (1.9–61)%; p = 0.002; p = 0.03] and correlated with % of TNFα+AM (r = 0.48; p = 0.0009) and CD8+ T cells (r = 0.44; p = 0.0029). In BAL, the CD14+SOCS3+ EVs/μL were increased in SC [33 (21–74)] compared to S [16 (8–37); p = 0.03] and NS [9 (7–21); p = 0.003]. Conversely, miRNA-19a-3p and miRNA-221-3p expression were increased in S when compared to SC [19 (2–53) vs. 3 (0.6–8); p = 0.03 and 3 (0.005–9.6) vs. 0.2 (0.08–0.7); p = 0.05].ConclusionsThe suppressor function of SOCS3 in COPD seems to be overridden by other factors and does not follow the animal-model paradigm. Expression of SOCS3 in BAL macrophage-derived EVs might be useful to assess the degree of inflammation and possible progression of COPD. Downregulation of SOCS3, by miRNA, in smokers without COPD might contribute to the risk of developing cancer in these patients.

Objective To synthesise the available evidence on physical factors, such as muscle strength and power, body mass index and their association with older adults’ self-reported and performance-based mobility outcomes. Method This review followed the Askey and O'Malley framework. We systematically searched PubMed, EMBASE, PsychINFO, Web of Science, AgeLine, Allied and Complementary Medicine Database, and Cumulative Index to Nursing and Allied Health Literature databases, from Jan. 2000 to Jan. 2022. Teams of two reviewers independently conducted title, abstract, full-text screening, and data extraction using predefined inclusion and exclusion criteria. Result A total of 239 quantitative articles, mostly cross-sectional design, conducted in 32 countries were included in this review. We identified 18 physical factors significantly associated with mobility outcomes in the expected direction. Muscle strength, body composition, falls (number and history of), and chronic conditions (number of and type) were the most studied physical factors. Conclusion Older adults with muscle weakness, weight concerns, history of falls, and chronic conditions had poorer mobility outcomes, such as slower gait speed, poor balance, limited community mobility and poor driving outcomes compared to their counterparts. Studies exploring the role of physical factors on the use of an assisted device, transportation, or driving, are limited.

ObjectivesT-helper 17 cell-mediated response and their effector IL-17 cytokine induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major cause of COVID-19 disease severity and death. Therefore, the study aimed to determine if IL-17 level in saliva mirrors its circulatory level and hence can be used as a non-invasive biomarker for disease severity.MethodsInterleukin-17 (IL-17) level was evaluated by ELISA in saliva and blood of 201 adult COVID-19 patients with different levels of severity. The IL-17 saliva level was also associated with COVID-19 disease severity, and need for mechanical ventilation and/or death within 29 days after admission of severe COVID-19 patients.ResultsWe found that IL-17 level in saliva of COVID-19 patients reflected its circulatory level. High IL-17 level in saliva was associated with COVID-19 severity (P<0.001), need for mechanical ventilation (P = 0.002), and/or death by 29 days (P = 0.002), after adjusting for patients’ demographics, comorbidity, and COVID-19 serum severity markers such as D-Dimer, C-reactive protein, and ferritin.ConclusionWe propose that saliva IL-17 level could be used as a biomarker to identify patients at risk of developing severe COVID-19.