G-CSFR antagonism reduces neutrophilic inflammation during pneumococcal and influenza respiratory infections without compromising clearance

Abstract

Excessive neutrophilic inflammation can contribute to the pathogenesis of pneumonia. Whilst anti-inflammatory therapies such as corticosteroids are used to treat excessive inflammation, they do not selectively target neutrophils and may compromise antimicrobial or antiviral defences. In this study, neutrophil trafficking was targeted with a granulocyte-colony stimulating factor receptor monoclonal antibody (G-CSFR mAb) during Streptococcus pneumoniae (serotype 19F) or influenza A virus (IAV, strain HKx31) lung infection in mice. Firstly, we demonstrated that neutrophils are indispensable for the clearance of S. pneumoniae from the airways using an anti-Ly6G monoclonal antibody (1A8 mAb), as the complete inhibition of neutrophil recruitment markedly compromised bacterial clearance. Secondly, we demonstrated that G-CSF transcript lung levels were significantly increased during pneumococcal infection. Prophylactic or therapeutic administration of G-CSFR mAb significantly reduced blood and airway neutrophil numbers by 30–60% without affecting bacterial clearance. Total protein levels in the bronchoalveolar lavage (BAL) fluid (marker for oedema) was also significantly reduced. G-CSF transcript levels were also increased during IAV lung infection. G-CSFR mAb treatment significantly reduced neutrophil trafficking into BAL compartment by 60% and reduced blood neutrophil numbers to control levels in IAV-infected mice. Peak lung viral levels at day 3 were not altered by G-CSFR therapy, however there was a significant reduction in the detection of IAV in the lungs at the day 7 post-infection phase. In summary, G-CSFR signalling contributes to neutrophil trafficking in response to two common respiratory pathogens. Blocking G-CSFR reduced neutrophil trafficking and oedema without compromising clearance of two pathogens that can cause pneumonia.

Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19

“…In influenza virus infections, neutrophils may promote clearance, or aggravate pathology, via a feedforward inflammatory circuit 54 , 55 . The cytokine G-CSF and the chemokine CXCL4, which are produced by multiple types of epithelial and endothelial cells of influenza virus-infected lungs, promote neutrophil mobilization from the bone marrow to the inflamed lung 56 , 57 . Several other neutrophil-recruiting chemokines are released by influenza virus-infected epithelial cells, alveolar macrophages and interstitial macrophages (Fig.…”

G‐CSFR antagonism reduces mucosal injury and airways fibrosis in a virus‐dependent model of severe asthma

“…For the TGFβ assay in panel (b), n = 8 for all groups. *P < .05, one-way ANOVA versus VEH; # P < .05, one-way ANOVA versus HDMIAV_ISO anti-viral immunity and viral clearance in an acute IAV infection model (Wang, Aloe, et al, 2019). Another potential complication of IAV infections is the increased susceptibility to secondary bacterial infections such as pneumococcus.…”

“…Consistent with this finding, sputum G‐CSF protein levels were significantly higher in asthmatic patients with neutrophil‐dominant inflammation (Kim et al, 2020). We have recently shown that influenza A virus significantly increased blood and lung neutrophil numbers at day 3 post infection in a manner that was suppressed with anti‐GCSFR treatment (Wang, Aloe, et al, 2019). These findings have guided our treatment protocol for this study where anti‐G‐CSFR was delivered during the peak blood granulocytic phase (at days 2 and 5 post influenza infection) as a strategy to block the peak viral‐mediated systemic and local neutrophil response.…”

G-CSF and GM-CSF Are Different. Which One Is Better for COVID-19?

“…For example, Jing and colleagues [ 20 ] reported G-CSF increases lung injury in a mouse model of acute renal injury. Wang et al [ 21 , 22 ] reported blocking the G-CSF receptor in mouse models of infection and asthma reduced neutrophil infiltration and neutrophil-mediated inflammation. Tsantikos and associates [ 23 ] reported G-CSF was important in the pathogenesis of chronic obstructive pulmonary disease in some persons.…”