Inhibiting Bruton’s tyrosine kinase rescues mice from lethal influenza-induced acute lung injury

Abstract

Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza-infected patients. Previous experiments in our laboratory indicate that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury in mice; therefore, we sought to determine if blocking Btk activity has a protective effect in the lung during influenza-induced inflammation. The Btk inhibitor ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72 h after lethal infection with IAV. Our data indicate that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but also had a dramatic effect on morphological changes to the lungs, in IAV-infected mice. Attenuation of lung inflammation indicative of acute lung injury, such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of the inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1, strongly suggests amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps released into the lung in vivo and neutrophil extracellular trap formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients

“…Control mice developed respiratory failure, along with histological and computed tomography findings consistent with lung injury, in sharp contrast to the mice that received ibrutinib. 1 Control mice also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss, and all survived. 1 Notably, mice treated with ibrutinib also showed decreased inflammatory cell infiltration, as well as proinflammatory cytokines in lung tissues, that included proinflammatory and chemoattractant cytokines, such as IL-1b, IL-6, KC/CXCL1, TNF-a, and MCP-1, in SARS-Cov-1 and SARS-CoV-2 patients.…”

“…The potential for ibrutinib to abrogate pulmonary inflammatory cytokines, lung injury, and death was demonstrated in a highly relevant lethal flu animal model. 1 Therefore, we sought to clarify the impact of ibrutinib in COVID-19 patients. We care for 600 to 800 Waldenstrom macroglobulinemia (WM) patients each year, ;300 of whom are on a BTK inhibitor.…”

Effects of BTK signalling in pathogenic microorganism infections

“…Although the effects of Btk signalling on pathogenic microorganism infections are not exactly consented upon, there is no doubt about its importance in maintaining the balance of the immune microenvironment. Many studies have shown that enhanced Btk function plays an important role in inflammatory diseases, such as IAV‐induced acute pneumonia . Therefore, we can control inflammatory processes by regulating Btk activity during different periods of disease to alleviate tissue damage and avoid organ failure.…”

“…In addition, the latest experimental evidence indicates that Btk is involved in influenza A virus (IAV) infection‐associated acute lung injury. Blocking Btk activity reduces weight loss, increases survival and minimizes morphological changes in IAV infection, suggesting that immunomodulatory treatment targeting Btk is an effective approach for controlling influenza‐induced lung injury …”

“…27 Moreover, the signalling of latent membrane protein 2A that immunomodulatory treatment targeting Btk is an effective approach for controlling influenza-induced lung injury. 34 In contrast, selective impairments of DC function are observed in response to oral poliovirus vaccine (OPV) and influenza virus H1N1. 35 Upon OPV stimulation, monocyte-derived DCs from XLA patients behave in a dysmature manner and show a significantly decreased production of interferon (IFN)-α2, IFN-β and IFN-λ1, while they are normal in their response to H1N1.…”