IL-37 Causes Excessive Inflammation and Tissue Damage in Murine Pneumococcal Pneumonia

Abstract

Streptococcus pneumoniae infections can lead to severe complications with excessive immune activation and tissue damage. Interleukin-37 (IL-37) has gained importance as a suppressor of innate and acquired immunity, and its effects have been therapeutic as they prevent tissue damage in autoimmune and inflammatory diseases. By using RAW macrophages, stably transfected with human IL-37, we showed a 70% decrease in the cytokine levels of IL-6, TNF-α, and IL-1β, and a 2.2-fold reduction of the intracellular killing capacity of internalized pneumococci in response to pneumococcal infection. In a murine model of infection with S. pneumoniae, using mice transgenic for human IL-37b (IL-37tg), we observed an initial decrease in cytokine expression of IL-6, TNF-α, and IL-1β in the lungs, followed by a late-phase enhancement of pneumococcal burden and subsequent increase of proinflammatory cytokine levels. Additionally, a marked increase in recruitment of alveolar macrophages and neutrophils was noted, while TRAIL mRNA was reduced 3-fold in lungs of IL-37tg mice, resulting in necrotizing pneumonia with augmented death of infiltrating neutrophils, enhanced bacteremic spread, and increased mortality. In conclusion, we have identified that IL-37 modulates several core components of a successful inflammatory response to pneumococcal pneumonia, which lead to increased inflammation, tissue damage, and mortality.

Spectrum of pathogen- and model-specific histopathologies in mouse models of acute pneumonia

“…Clearly, in addition to descriptive or semiquantitative histology, a number of other parameters may be useful for quantitative comparisons between experimental groups to determine the role of specific cell types, molecules, and therapeutic interventions, depending on the strategy and goal of the study [ 44 ]. Such parameters could include flow cytometric immune cell identifications and quantifications, ELISA or quantitative RT-PCR for the probing of cytokines, chemokines or matrix proteins involved in lung pathology and remodeling, and plaque/colony forming assays for the identification or quantification of pathogens, as previously published for most of the models used here [ 38 , 41 , 42 , 51 – 53 , 86 , 87 ]. All of these methods, however, lack the spatial resolution that only histological assessments offer.…”

Age-Dependent Progression of SARS-CoV-2 Infection in Syrian Hamsters

“…as described previously [ 34 ]. Lung inflammation scores were determined as (0) absent, (1) minimal, (2) mild, (3) moderate, or (4) severe, and quantified as described previously [ 35 ]. Immune cell influx scores and edema scores were rated from (0) absent to (1) sporadic, (2) mild, (3) moderate, or (4) severe.…”

Untitled

“…We read with great interest the paper presented in the current issue of the Journal of innate immunity by Schauer, et al [1] showing the pathogenic role of Interleukin-37 (IL-37) in the murine model of Streptococcus pneumoniae pneumonia. This study found that recruitment of alveolar macrophages and neutrophils was markedly increased in the mice transgenic for human IL-37b (IL-37tg) with heavier pneumococcal burden, resulting in necrotizing pneumonia with augmented death of infiltrating neutrophils, and leading to enhanced inflammation, tissue damage, and mortality.…”

“…However, several published studies displayed IL-37tg mice had less severe inflammation in models of endotoxin shock, colitis, obesity-induced inflammation and myocardial inflammatory [2][3][4][5]. The authors argued that it is mainly due to the core components of a successful inflammatory response to pneumococcal pneumonia, which lead to increased inflammation, tissue damage, and mortality and is modulated by IL-37 cytokine [1].…”