Ravi, V. R. | bioRxiv Science

bioRxiv2024

Lung CD4+ resident memory T cells use airway secretory cells to stimulate and regulate neutrophilic allergic airways disease.

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancement will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4+ resident memory TRM cells, including unconventional ROR{gamma}tnegative/low TH17 cells. Acute OVA challenge instigates IL-17A secretion from these TRM cells, driving CXCL5 production from Muc5achigh airway secretory cells, leading to destructive airway neutrophilia. The TRM- and epithelial-cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing TRM cells towards TH2 and TH1 fates, so that the TH1-related IFN-{gamma} suppresses IL-17A-driven, CXCL5-mediated airway neutrophilia. Concordantly, in vivo IFN-{gamma} supplementation improves disease outcomes. Thus, using our model of neutrophilic asthma we identify lung epithelial-CD4+ TRM cell crosstalk as a key rheostat of allergic airway neutrophilia. HighlightsO_LIRecurrent OVA inhalation experience predisposes mice to allergic airways neutrophilia C_LIO_LINeutrophil-prone lungs harbor CD4+ TRM cells including ROR{gamma}tnegative/low TH17 cells C_LIO_LIMuc5achigh secretory cells instruct CD4+ TRM fates and neutrophilia via MHC-II and CXCL5, respectively C_LIO_LIProphylactic or therapeutic delivery of IFN-{gamma} curbs allergic airway neutrophilia C_LI

immunology↗

bioRxiv2022

Neutrophil-driven cardiac damage during invasive Streptococcus pneumoniae infection is regulated by CD73

Streptococcus pneumoniae (pneumococcus)-induced cardiac events are one of the life-threatening infection outcomes of invasive pneumococcal disease. S. pneumoniae has the ability to invade the myocardium and damage cardiomyocytes, however the contribution of the immune response during this process is not fully understood. We previously found that polymorphonuclear cells (PMNs) are crucial for host defense against S. pneumoniae lung infection and that extracellular adenosine (EAD) production, by exonucleosidases CD39 and CD73, controlled the anti-bacterial functions of these cells. The objective of this study was to explore the role of PMNs and the EAD-pathway in host cardiac damage during invasive pneumococcal infection. Upon intra-peritoneal (i.p.) injection with invasive S. pneumoniae TIGR4 strain, hearts of C57BL/6 mice showed an increased influx of PMNs as determined by flow cytometry. However, the increased PMN numbers failed to contain the bacterial burden in the heart and showed positive correlation with serum levels of the cardiac damage marker Troponin-1. Influx of PMNs into the heart was associated with constant presence of neutrophil degranulation products in the cardiac tissue. Depletion of PMNs prior infection reduced pneumococcal burden in the heart and lowered the Troponin-1 levels thus, indicating their role in cardiac damage. While exploring the mechanisms underlying the damaging PMN response, we found that by 24hpi, there was a significant reduction in the expression of CD39 and CD73 on cardiac PMNs. The role of CD73 in regulating cardiac damage was tested in vivo using CD73-/- mice which had significantly higher bacterial burden and cardiac damage compared to wild type mice despite similar PMN numbers. The role of CD73 expression on PMNs was also tested ex vivo using the HL-1 cardiomyocyte cell line which upon S. pneumoniae infection, showed increased cell death in presence of CD73-/- PMNs. Our findings have identified a detrimental role for PMNs in cardiac damage during invasive pneumococcal infection that is in part driven by reduced expression of EAD-producing enzymes in late disease stages.

immunology↗