Nociceptin reduces the inflammatory immune microenvironment in a conventional murine model of airway hyperresponsiveness.

BACKGROUND: Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are involved in airway hyperresponsiveness (AHR) and inflammation. However, the role of nociceptin at modulating the inflammatory immune microenvironment in asthma is still unclear. OBJECTIVE: To understand the role of N/OFQ in the regulation of a Th2-like environment, we used a conventional murine model of AHR. METHODS: Balb/c and CD1 mice were sensitized to ovalbumin (OVA) and treated with saline solution or N/OFQ, at days 0 and 7. A group of Balb/c mice were killed at 7 and 14 days from the first sensitization for the inflammatory profile evaluation while a group of Balb/c and CD1 mice were aerosol-challenged from day 21 to 23 with OVA and killed 24 h later for functional evaluations. RESULTS: In OVA-sensitized mice, N/OFQ significantly reduced IL-4+ CD4+ T cells in lymph nodes (LN) and IL-13 in the lungs, while it induced IFN-γ increase in the lung. The efflux of dendritic cells (DCs) to the mediastinic LN and into the lung of OVA-sensitized mice was reduced in N/OFQ-treated and sensitized mice. N/OFQ reduced the expression of CD80 on DCs, indicating its ability to modulate the activation of DCs. In a less prone Th2-like environment mice strain, such as CD1 mice, N/OFQ did not modify lung resistances as observed in BALB/c mice. Finally, spectroscopic data showed the N/OFQ was able to interact onto the membrane of DCs obtained from Balb/c rather than CD1 mice, indicating its ability to modulate AHR in a Th2-like environment with a direct activity on DCs. CONCLUSIONS AND CLINICAL RELEVANCE: Our data confirmed the capability of N/OFQ to modulate the immune microenvironment in the lung of Th2-biased, OVA-sensitized Balb/c mice, suggesting N/OFQ-NOP axis as a novel pharmacological tool to modulate the inflammatory immune microenvironment in asthma.

Similar programmed death ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer.

Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). Alveolar macrophage (AM)-derived PD-L1 binds to its receptor, PD-1, on surveilling lymphocytes, leading to lymphocyte exhaustion. Increased PD-L1 expression is associated with cigarette smoke (CS)-exposure. However, the PD-L1 role in CS-associated lung diseases associated with NSCLC, such as chronic obstructive pulmonary disease (COPD), is still unclear. In two different cohorts of ever smokers with COPD or NSCLC, and ever and never smoker controls, we evaluated PD-L1 expression: (1) via cutting-edge digital spatial proteomic and transcriptomic profiling (Geomx) of formalin-fixed paraffin-embedded (FFPE) lung tissue sections (n = 19); and (2) via triple immunofluorescence staining of bronchoalveolar lavage (BAL) AMs (n = 83). PD-L1 mRNA expression was also quantified in BAL AMs exposed to CS extract. PD-L1 expression was increased in the bronchiolar wall, parenchyma, and vascular wall from mild-moderate (GOLD 1-2) COPD patients compared to severe-very severe (GOLD 3-4) COPD patients and controls. Within all the COPD patients, PD-L1 protein expression was associated with upregulation of genes involved in tumor progression and downregulation of oncosuppressive genes, and strongly directly correlated with the FEV1% predicted, indicating higher PD-L1 expression in the milder vs. more severe COPD stages. In bronchioles, PD-L1 levels were strongly directly correlated with the number of functionally active AMs. In BAL, we confirmed that AMs from patients with both GOLD 1-2 COPD and NSCLC had the highest and similar, PD-L1 expression levels versus all the other groups, independently from active cigarette smoking. Intriguingly, AMs from patients with more severe COPD had reduced AM PD-L1 expression compared to patients with mild COPD. Acute CS extract stimulation increased PD-L1 mRNA expression only in never-and not in ever-smoker AMs. Lungs from patients with mild COPD and NSCLC are characterized by a similar strong PD-L1 expression signature in bronchioles and functionally active AMs compared to patients with severe COPD and controls. Active smoking does not affect PD-L1 levels. These observations represent a new resource in understanding the innate immune mechanisms underlying the link between COPD and lung cancer onset and progression and pave the way to future studies focused on the mechanisms by which CS promotes tumorigenesis and COPD.