Galectin-3 Enhances Avian H5N1 Influenza A Virus–Induced Pulmonary Inflammation by Promoting NLRP3 Inflammasome Activation

Abstract

Highly pathogenic avian influenza A H5N1 virus causes pneumonia and acute respiratory distress syndrome in humans. Virus-induced excessive inflammatory response contributes to severe disease and high mortality rates. Galectin-3, a β-galactoside-binding protein widely distributed in immune and epithelial cells, regulates various immune functions and modulates microbial infections. Here, we describe galectin-3 up-regulation in mouse lung tissue after challenges with the H5N1 influenza virus. We investigated the effects of endogenous galectin-3 on H5N1 infection and found that survival of galectin-3 knockout (Gal-3KO) mice was comparable with wild-type (WT) mice after infections. Compared with infected WT mice, infected Gal-3KO mice exhibited less inflammation in the lungs and reduced IL-1β levels in bronchoalveolar lavage fluid. In addition, the bone marrow-derived macrophages (BMMs) from Gal-3KO mice exhibited reduced oligomerization of apoptosis-associated speck-like proteins containing caspase-associated recruitment domains and secreted less IL-1β compared with BMMs from WT mice. However, similar levels of the inflammasome component of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) were observed in two genotypes of BMMs. Co-immunoprecipitation data indicated galectin-3 and NLRP3 interaction in BMMs infected with H5N1. An association was also observed between galectin-3 and NLRP3/apoptosis-associated speck-like proteins containing caspase-associated recruitment domain complex. Combined, our results suggest that endogenous galectin-3 enhances the effects of H5N1 infection by promoting host inflammatory responses and regulating IL-1β production by macrophages via interaction with NLRP3.

MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways

“…Whether the non-canonical (caspase 11-mediated) NLRP3 inflammasome pathway is altered in MGL1 −/− Mφ remains to be confirmed. Our findings are in line with those previously reported showing that other lectins, such as galectin-3, are able to trigger NLRP3 activation in the context of liver diseases and influenza infection [52,56].…”

Rhein Suppresses Lung Inflammatory Injury Induced by Human Respiratory Syncytial Virus Through Inhibiting NLRP3 Inflammasome Activation via NF-κB Pathway in Mice

“…The activation and subsequent processing of Caspase-1 as well as the secretion and release of cytokine IL-1 family members was regulated by NLRP3 inflammasome and the downstream associated protein ASC participating in innate immune defense Poudel and Gurung, 2018). In previous researches, it was suggested that IL-1b family inflammatory elements play an important role in acute and chronic inflammation and in the meantime, NLRP3 inflammasome pathway is one of the key signaling pathways to lead to excessive inflammation (Pinkerton et al, 2017;Chen et al, 2018;Gugliandolo et al, 2018). Besides, NF-kB is a vital family of transcription factors, which is widely involved in a variety of biological processes, including inflammation.…”

Hyperinflammation and Fibrosis in Severe COVID-19 Patients: Galectin-3, a Target Molecule to Consider

“…Moreover, previous SARS-CoV infection also runs with a strong inflammatory response and fibrosis (25)(26)(27) highlighting the importance of this approach for SARS-CoV-2. Mechanistically, it has been proved that SARS-CoV can activate NLRP3 inflammasome (28) something that occurs in H5N1 influenza infection as well in a gal3-dependent manner driving IL-1β production (29). Additionally, NLRP3 activation controls serum levels of gal3 (30).…”