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.
Highlights
chronic obstructive pulmonary disease (COPD) will be the third-leading cause of death worldwide by 2030 [1]
We show that human macrophages rapidly and profoundly upregulate Pellino-1 in response to LPS and Non-typeable Haemophilus influenzae (NTHi), suggesting a potential role for this protein in the initial cellular immune response to NTHi
Our work suggests that Pellino-1 is a key component of the airway immune response to NTHi and that therapeutically targeting Pellino-1 may enhance clearance of NTHi in patients with chronic inflammatory disease who are at risk of infection induced exacerbations
Summary
COPD will be the third-leading cause of death worldwide by 2030 [1]. Recurrent bacterial and viral infections are a significant cause of comorbidity in COPD, resulting in accelerated decline in lung function and posing a major economic and personal burden [2]. The most common colonizing microorganism is NTHi, found in the lower respiratory tract of 30% of individuals with COPD [3]. The primary cellular immune response to NTHi is the alveolar macrophage (AM), but in COPD, they often fail to clear bacteria from the airway [7]. NTHi infection leads to a Toll-like receptor (TLR)-dependent immune response in AMs, including the release of proinflammatory cytokines such as CXCL8 [8], which
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