AMG487 alleviates influenza A (H1N1) virus-induced pulmonary inflammation through decreasing IFN--producing lymphocytes and IFN- concentrations

Background and Purpose: Severe influenza virus-infected patients have high systemic levels of Th1 cytokines (including IFN-gamma). Intrapulmonary IFN-gamma increases pulmonary IFN-gamma-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-gamma concentrations increased, while pulmonary H1N1 viral titres and neutrophils decreased. Both anti-IFN-gamma 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-gamma, IP-10, and IFN-gamma-producing lymphocytes and activation of the Jak2-Stat1 pathways in mouse lungs, which were inhibited by AMG487. Anti-IFN-gamma decreased IFN-gamma and IFN-gamma-producing lymphocytes on Day-5 post-infection. AMG487 but not anti-IFN-gamma decreased viral titres in mouse lung homogenates or BALF. Higher virus load did not increase pulmonary inflammation and IFN-gamma concentrations when mice were treated with AMG487. Conclusion and Implications: AMG487 may ameliorate H1N1 virus-induced pulmonary inflammation through decreasing IFN-gamma-producing lymphocytes rather than reducing viral loads or neutrophils.