AMG487 alleviates influenza A (H1N1) virus‐induced pulmonary inflammation through decreasing IFN‐γ‐producing lymphocytes and IFN‐γ concentrations
Wenbin Ding, Runfeng Li, Tongtong Song, Zifeng Yang, Dongting Xu, Chuqin Huang, Shuirong Shen, Nanshan Zhong, Kefang Lai, Zheng Deng- Pharmacology
Background and Purpose
Severe influenza virus‐infected patients have high systemic levels of Th1 cytokines (including IFN‐γ). Intrapulmonary IFN‐γ increases pulmonary IFN‐γ‐producing T lymphocytes through the CXCR3 pathway. Virus‐infected mice lacking IP‐10/CXCR3 demonstrate lower pulmonary neutrophilic inflammation. AMG487, an IP‐10/CXCR3 antagonist, ameliorates virus‐induced lung injury in vivo through decreasing viral loads. This study examined whether AMG487 could treat H1N1 virus‐induced mouse illness through reducing viral loads or decreasing the number of lymphocytes or neutrophils.
Experimental Approach
Here, we studied the above‐mentioned effects and underlying mechanisms in vivo.
Key Results
H1N1 virus infection caused bad overall condition and pulmonary inflammation characterized by the infiltration of lymphocytes and neutrophils. From Day‐5 to Day‐10 post‐virus infection, bad overall condition, pulmonary lymphocytes, and IFN‐γ concentrations increased, while pulmonary H1N1 viral titres and neutrophils decreased. Both anti‐IFN‐γ and AMG487 alleviated virus infection‐induced bad overall condition and pulmonary lymphocytic inflammation. Pulmonary neutrophilic inflammation was mitigated by AMG487 on Day‐5 post‐infection, but was not mitigated by AMG487 on Day‐10 post‐infection. H1N1 virus induced increases of IFN‐γ, IP‐10, and IFN‐γ‐producing lymphocytes and activation of the Jak2‐Stat1 pathways in mouse lungs, which were inhibited by AMG487. Anti‐IFN‐γ decreased IFN‐γ and IFN‐γ‐producing lymphocytes on Day‐5 post‐infection. AMG487 but not anti‐IFN‐γ decreased viral titres in mouse lung homogenates or BALF. Higher virus load did not increase pulmonary inflammation and IFN‐γ concentrations when mice were treated with AMG487.
Conclusion and Implications
AMG487 may ameliorate H1N1 virus‐induced pulmonary inflammation through decreasing IFN‐γ‐producing lymphocytes rather than reducing viral loads or neutrophils.