Pulmonary immune cells and inflammatory cytokine dysregulation are associated with mortality of IL-1R1 -/-mice infected with influenza virus (H1N1).

Lei Guo,Xi Wang,Ruotong Ning ,Junjie Mei ,Haitao Fan ,Jiaqi Li ,Huiwen Zheng ,Jingjing Wang ,Yancui Wang ,Long-Ding Liu

doi:10.24272/j.issn.2095-8137.2017.035

Abstract

Respirovirus infection can cause viral pneumonia and acute lung injury (ALI). The interleukin-1 (IL-1) family consists of proinflammatory cytokines that play essential roles in regulating immune and inflammatory responses in vivo. IL-1 signaling is associated with protection against respiratory influenza virus infection by mediation of the pulmonary anti-viral immune response and inflammation. We analyzed the infiltration lung immune leukocytes and cytokines that contribute to inflammatory lung pathology and mortality of fatal H1N1 virus-infected IL-1 receptor 1 (IL-1R1) deficient mice. Results showed that early innate immune cells and cytokine/chemokine dysregulation were observed with significantly decreased neutrophil infiltration and IL-6, TNF-α, G-CSF, KC, and MIP-2 cytokine levels in the bronchoalveolar lavage fluid of infected IL-1R1-/- mice in comparison with that of wild type infected mice. The adaptive immune response against the H1N1 virus in IL-1R1-/- mice was impaired with downregulated anti-viral Th1 cell, CD8+ cell, and antibody functions, which contributes to attenuated viral clearance. Histological analysis revealed reduced lung inflammation during early infection but severe lung pathology in late infection in IL-1R1-/- mice compared with that in WT infected mice. Moreover, the infected IL-1R1-/- mice showed markedly reduced neutrophil generation in bone marrow and neutrophil recruitment to the inflamed lung. Together, these results suggest that IL-1 signaling is associated with pulmonary anti-influenza immune response and inflammatory lung injury, particularly via the influence on neutrophil mobilization and inflammatory cytokine/chemokine production.

Highlights

Respirovirus infection causes respiratory illness that affects millions of people every year (Coates et al, 2015)
Survival and viral loads in H1N1-infected mouse lungs The deaths of wild type (WT) mice were primarily observed at 7–9 dpi, with no deaths occurring after this time (Figure 1A), whereas the IL-1 receptor 1 (IL-1R1)-/- mice began to die at 5 dpi
The role of IL-1R1 signaling in the morbidity and mortality of IAV infection was previously investigated (Schmitz et al, 2005), and our results confirm the importance of IL-1R1 signaling in protecting mice against fatal IAV infection and moderating the inhibition of viral replication

Summary

Introduction

Respirovirus infection causes respiratory illness that affects millions of people every year (Coates et al, 2015). Viral infection triggers cellular immune pathways to express abundant inflammatory cytokines and chemokines, including TNF-α, IL1α/β, IL-2, IL-4, IL-6, IFN-α/β, CXCL-1/2, CXCL-9/10, MIP-1/2, and MCP-1, in the respiratory tract and alveolar spaces (Kohlmeier & Woodland, 2009; Sanders et al, 2011). These cytokines, in turn, recruit innate immune cells such as macrophages, granulocytes, dendritic cells (DCs), and natural killer (NK) cells into the infected lung to exert anti-viral innate immune responses. Our results suggest that the lack of IL-1 signaling induces an impaired innate and adaptive immune response, together with an increased inflammation response and immunopathology following fatal IAV infection in the infected mouse lung, and contributes to impaired viral clearance and high mortality

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Conclusion