Targeting S100A9 to prevent Streptococcus pneumoniae-induced allergic asthma exacerbation

Abstract

Abstract The alarmin S100 calcium-binding protein A9 (S100A9) plays a role in the immunopathology of lung diseases such as asthma and pneumonia. We hypothesized that acute pneumonia induced by S. pneumoniae exacerbates asthma through S100A9 induction that increase neutrophilic inflammation and NET production. C57BL/6 Wild Type (WT) animals and mice deficient for the expression of S100A9 (S100A9 −/−) were sensitized and challenged with ovalbumin (OVA) and infected or not with S. pneumoniae during the challenge. In WT mice, the comorbidity resulted in a significant increase in neutrophil recruitment in the bronchoalveolar lavage fluid (BALF) accompanied by an increased perivascular and peribronchial leukocyte infiltration, S100A9 secretion and NET production in the lungs compared to the WT mice exposed only to the allergen. During the comorbidity, S100A9 −/−mice exhibited significant reduction in the levels of neutrophil chemoattractant CXCL1 and neutrophilic inflammation in the BALF as well as perivascular and peribronchial leukocyte infiltration into the lungs compared to their WT counterpart. Moreover, during the comorbidity, S100A9 −/−mice showed an increase in neutrophil death. Pharmacological intervention with tasquinimod, an inhibitor of S100A9 signaling, or BB Cl-amidine, an inhibitor of NET, protected mice from neutrophilic inflammation and NET production and reduced lung inflammation during the asthma and acute pneumonia comorbidity.Our results provided evidence that S100A9 might be a therapeutic target in severe asthma triggered by S. pneumoniae infection. Financial support: The Sao Paulo Research Foundation (FAPESP), grants 2017/21629­5 (VLDB) and 2019/09881-6 (TFCF-S), and the Brazilian National Council for Scientific and Technological Development (CNPq), grant 142139/2019-0 (MMMB).