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The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection
Journal of Biomedical Science
  • Sue-Jane Lin, Chang Gung University
  • Ming Lo, National Taiwan University
  • Rei-Lin Kuo, Chang Gung University
  • Shin-Ru Shih, Chang Gung University
  • David M. Ojcius, University of California, Merced
  • Jean Lu, Academia Sinica
  • Chien-Kuo Lee, National Taiwan University
  • Hui-Chen Chen, China Medical University
  • Meei Yun Lin, Chang Gung University
  • Chuen-Miin Leu, National Yang-Ming University
  • Chia-Ni Lin, Chang Gung University
  • Ching-Hwa Tsai, National Taiwan University
David M. Ojcius: 0000-0003-1461-4495
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Background: Highly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection. Results: We established H1N1 IAV-infected mouse models using three viruses of varying pathogenicity and noted the accumulation of a defined Gr1 + CD11b + myeloid population correlating with the pathogenicity. Herein, we reported that CCR2+ inflammatory monocytes are the major cell compartments in this population. Of note, impaired clearance of the high pathogenicity virus prolonged IFN expression, leading to CCR2+ inflammatory monocytes amplifying their own recruitment via an interferon-alpha/beta receptor 1 (IFNAR1)-triggered chemokine loop. Blockage of IFNAR1-triggered signaling or inhibition of viral replication by Oseltamivir significantly suppresses the expression of CCR2 ligands and reduced the influx of CCR2+ inflammatory monocytes. Furthermore, trafficking of CCR2+ inflammatory monocytes from the bone marrow to the lung was evidenced by a CCR2-dependent chemotaxis. Importantly, leukocyte infiltration, cytokine storm and expression of iNOS were significantly reduced in CCR2-/- mice lacking infiltrating CCR2+ inflammatory monocytes, enhancing the survival of the infected mice. Conclusions: Our results indicated that uncontrolled viral replication leads to excessive production of inflammatory innate immune responses by accumulating CCR2+ inflammatory monocytes, which contribute to the fatal outcomes of high pathogenicity virus infections.
Citation Information
Sue-Jane Lin, Ming Lo, Rei-Lin Kuo, Shin-Ru Shih, et al.. "The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection" Journal of Biomedical Science Vol. 21 Iss. 99 (2014) p. 1 - 18 ISSN: 1021-7770
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