Pellino-1 Regulates the Responses of the Airway to Viral Infection

Abstract

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1 −/− mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.

Pellino1 deficiency reprograms cardiomyocytes energy metabolism in lipopolysaccharide-induced myocardial dysfunction

“…Moreover, combined with restoration of the abnormal metabolism and disturbed expression of transcription factors involved in cardiac fuel and energy metabolism, silencing Pellino1 showed cardioprotective value, revealing that silencing Pellino1 could be a promising therapeutic strategy against LPS-induced myocarditis or other pathologies in future clinical trials. In addition, considering the pro-inflammatory role of Pellino1 reported in the sepsis-induced lung injury model and COPD-induced inflammatory airway responses, silencing Pellino1 can also ameliorate acute or chronic lung pneumonia (Liu et al 2021 ; Marsh et al 2020 ; Hughes et al 2019 ). Other than the heart and lung, the regulatory effects of Pellino1 on TLR/IL-1R signaling make it reasonable to assume that silencing Pellino1 may be targeted therapeutically in different inflammatory disorders associated with TLR/IL-1R signaling, which remains to be further explored in the future.…”

Dendritic Cell–Specific Role for Pellino2 as a Mediator of TLR9 Signaling Pathway

“…Pellino proteins play several important and nonredundant roles in various cells in the immune system. Pellino1 regulates various pathways in cells of different origin, such as macrophages ( 25 , 54 , 55 ), microglia ( 56 , 57 ), B cells ( 28 ), T cells ( 26 , 27 , 58 ), and epithelial cells of airways ( 59 ), whereas the role of Pellino2 and Pellino3 has been mostly characterized in macrophages ( 29 – 33 ). In this study, for the first time, to our knowledge, we show that Pellino2 plays a cell-specific role in DCs.…”

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…Pellino1 possesses a novel function in human viral pathogen infection (41,62,84,85) depending on TRIF. Pellino1, as a TLR3 positive regulator (18,37,86), is involved in modulating the production of proinflammatory cytokines (37,86) and induction of IFN-I in the TLR3 pathway (41,44,86,87). The deficiency of Pellino1 leads to inhibition of TLR3 and proinflammatory cytokines production but without impairing IFN antiviral induction under virus stimulation and TLR3 agonists in mice and primary bronchial epithelial cells (PBECs) (62,86).…”

“…In the TRIF-dependent interferon induction signaling (Figure 3), Pellino1 and Pellion3 display polar functions in the production of IFNs (41,44,86,87). The role of Pellino1 in the induction of IFNs seemed to be unclear.…”