IL‐27 mediates anti‐inflammatory effect in cigarette smoke induced emphysema by negatively regulating IFN‐γ producing cytotoxic CD8⁺T cells in mice

Abstract

Chronic airway inflammation mediated by CD8 + T lymphocytes contributes to the pathogenesis of Chronic obstructive pulmonary disease (COPD). Deciphering the fingerprint of the chronic inflammation orchestrated by CD8 + T cells may allow the development of novel approaches to COPD management. Here, the expression of IL-27 and IFN-γ + CD8 + Tc1 cells were evaluated in patients with COPD and in cigarette smoke-exposed mice. The production of IL-27 by marrow-derived dendritic cells (mDCs) in response to cigarette smoke extract (CSE) was assessed. The role of IL-27 in IFN-γ + CD8 + Tc1 cells was explored. We demonstrated that elevated IL-27 was accompanied by an exaggerated IFN-γ + CD8 + Tc1 response in a smoking mouse model of emphysema. We noted that lung dendritic cells were one of the main sources of IL-27 during chronic cigarette smoke exposure. Moreover, CSE directly induced the production of IL-27 by mDCs in vitro. IL-27 negatively regulated the differentiation of IFN-γ + CD8 + Tc1 cells isolated from cigarette smoke-exposed mice in a STAT1-and STAT3-independent manner. Systemic administration of recombinant IL-27 attenuated IFN-γ + CD8 + Tc1 response in the late phase of cigarette smoke exposure. Our results uncovered that IL-27 negatively regulates IFN-γ + CD8 + Tc1 response in the late stage of chronic cigarette smoke exposure, which may provide a new strategy for the antiinflammatory treatment of smoking-related COPD/emphysema.

Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug–Gene Networks: From Biology to Precision Therapeutics

“…The shift in macrophage subtype slant seen in the 3-month FCM data (Figure 8B; IGF2R − CD74 + subtype reduction, IGF2R + CD74 − subtype increase) was reflected in the plaque histology (Figure 8F), coinciding with the decreased circulating IL-6 (early, Figure 7G) and IFNγ (late, Figure 7G). On the contrary, potentially inflammation-resolving IL-10 and IL-27 [44][45][46] increased with BI-2536, albeit nonconcurrently (Figure 7G). Even when early IL-10 levels were almost equivalent (P=0.0688) between groups, IL-27 increased (P=0.0020; Figure 7G, upper panel) with BI-2536.…”

An updated advancement of bifunctional IL-27 in inflammatory autoimmune diseases

“…A smoking mouse model of emphysema reported high expression of IL-27, and strong CD8 + IFNγ + T-cell response ( 99 ). IL-27 stimulation with CD8 + IFNγ + T cells inhibited differentiation of CD8 + IFNγ + T cells, and injection of IL-27 into the mice attenuated CD8 + IFNγ + T-cell response after cigarette smoke exposure ( 99 ).…”

“…A smoking mouse model of emphysema reported high expression of IL-27, and strong CD8 + IFNγ + T-cell response ( 99 ). IL-27 stimulation with CD8 + IFNγ + T cells inhibited differentiation of CD8 + IFNγ + T cells, and injection of IL-27 into the mice attenuated CD8 + IFNγ + T-cell response after cigarette smoke exposure ( 99 ). Injection of IL-27 into the OVA-induced asthma mouse model showed a high percentage of Th1 and total memory T cells and lower expression of Th2-related cytokines IL-4, IL-5, and IL-13 ( 100 ).…”