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Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: Experimental Murine Data and Review of the Literature

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Abstract

The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys Cre/+ FoxO1 fl/fl mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys Cre/+ FoxO1 fl/fl mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.

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Acknowledgments

We would like to thank the staff of the Experimental Animal Center (USTC) for animal care. We thank the staff of the Core Facility Center for Life Sciences (USTC) for the help with the confocal microscope. We thank Dr. Bin Gao (NIH, Bethesda, Maryland) who kindly donated the Lys Cre/+ mice. We are grateful to Min Wu (North Dakota State University, Fargo, ND) for helpful discussions and reading of the manuscript.

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Authors and Affiliations

  1. Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China

    Yu-Chen Wang, Hong-Di Ma, Xue-Ying Yin, Yin-Hu Wang, Qing-Zhi Liu, Jing-Bo Yang & Zhe-Xiong Lian

  2. The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China

    Qing-Hua Shi & Baolin Sun

  3. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, 95616, USA

    M. Eric Gershwin

  4. Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, 230027, China

    Zhe-Xiong Lian

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  1. Yu-Chen Wang
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Ethical Approval

All procedures performed in studies involving animals were in accordance with the guidelines outlined in the Guide for the Care and use of Laboratory Animals, Laboratory Animal Center, School of Life Sciences, University of Science and Technology of China. The animal protocol was approved by The Institutional Animal Use and Care Committee of University of Science and Technology of China (Animal ethics approval number USTCACUC1501009). Every effort was made to avoid or minimize suffering and to improve animal welfare.

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The authors declare that they have no competing interests.

Financial Support

Financial support was provided by the National Basic Research Program of China (973 Program-2013CB944900), the National Natural Science Foundation of China (81130058, 81430034, 91542123), and the Research Fund for the Doctoral Program of Higher Education of China (RFDP 20133402110015).

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Wang, YC., Ma, HD., Yin, XY. et al. Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: Experimental Murine Data and Review of the Literature. Clinic Rev Allerg Immunol 51, 353–369 (2016). https://doi.org/10.1007/s12016-016-8531-1

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