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.
Keywords: AMG487; CXC chemokine receptor 3; influenza a virus; interferon-γ; interferon-γ-inducible protein 10.
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