Abstract
BackgroundStreptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia.MethodsMice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed.ResultsTreatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation.ConclusionsTaken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.
Highlights
Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis
Ibrutinib completely abrogated autophosphorylation of Bruton’s tyrosine kinase (Btk) Y223 in the murine macrophage cell line RAW264.7 stimulated with lipoteichoic acid (LTA) (Fig. 1a) and reduced tumor necrosis factor (TNF) secretion upon stimulation with S. pneumoniae or different concentrations of LTA (Fig. 1b-c)
At 21 h of LTA inflammation, alveolar macrophages (AM) and monocyte counts were similar between groups, but polymorphonuclear cells (PMN) numbers were reduced by ibrutinib treatment (p = 0.04) (Fig. 2b-d)
Summary
Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Several pattern recognition receptors contribute to the initiation of an inflammatory response to pneumococci, such as Toll-like receptor 2 (TLR2), TLR4, TLR9, triggering receptor expressed on myeloid cells (TREM)-1 and inflammasomes (van der Poll & Opal, 2009; Koppe de Porto et al Molecular Medicine (2019) 25:3 et al, 2012; Rabes et al, 2016; Hommes et al, 2014). Bruton’s tyrosine kinase (Btk) is a versatile signaling protein downstream several immune receptors (Weber et al, 2017), including TLR2, TLR4 and TLR9 (Liljeroos et al, 2007; Liu et al, 2011; Doyle et al, 2007), the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (Ito et al, 2015) and TREM-1 (Ormsby et al, 2011). The fact that expression of Btk is confined to immune cells, including B cells and innate immune cells such as macrophages, monocytes and PMN (Weber et al, 2017), makes Btk an interesting target for intervention of the exaggerated inflammatory response during pneumococcal pneumonia
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