AUTHOR=Hughes Bethany M. , Burton Charlotte S. , Reese Abigail , Jabeen Maisha F. , Wright Carl , Willis Jessica , Khoshaein Nika , Marsh Elizabeth K. , Peachell Peter , Sun Shao C. , Dockrell David H. , Marriott Helen M. , Sabroe Ian , Condliffe Alison M. , Prince Lynne R. TITLE=Pellino-1 Regulates Immune Responses to Haemophilus influenzae in Models of Inflammatory Lung Disease JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01721 DOI=10.3389/fimmu.2019.01721 ISSN=1664-3224 ABSTRACT=

Non-typeable Haemophilus influenzae (NTHi) is a frequent cause of lower respiratory tract infection in people with chronic obstructive pulmonary disease (COPD). Pellino proteins are a family of E3 ubiquitin ligases that are critical regulators of TLR signaling and inflammation. The aim of this study was to identify a role for Pellino-1 in airway defense against NTHi in the context of COPD. Pellino-1 is rapidly upregulated by LPS and NTHi in monocyte-derived macrophages (MDMs) isolated from individuals with COPD and healthy control subjects, in a TLR4 dependent manner. C57BL/6 Peli1−/− and wild-type (WT) mice were subjected to acute (single LPS challenge) or chronic (repeated LPS and elastase challenge) airway inflammation followed by NTHi infection. Both WT and Peli1−/− mice develop airway inflammation in acute and chronic airway inflammation models. Peli1−/− animals recruit significantly more neutrophils to the airway following NTHi infection which is associated with an increase in the neutrophil chemokine, KC, in bronchoalveolar lavage fluid as well as enhanced clearance of NTHi from the lung. These data suggest that therapeutic inhibition of Pellino-1 may augment immune responses in the airway and enhance bacterial clearance in individuals with COPD.