TY - JOUR
T1 - Critical role of zinc transporter (zip8) in myeloid innate immune cell function and the host response against bacterial pneumonia
AU - Hall, Sannette C.
AU - Smith, Deandra R.
AU - Dyavar, Shetty Ravi
AU - Wyatt, Todd A.
AU - Samuelson, Derrick R.
AU - Bailey, Kristina L.
AU - Knoell, Daren L.
N1 - Funding Information:
Research, The University of Nebraska Foundation, the Nebraska Banker’s Fund, and by the NIH, National Center for Research Resources Shared Instrument Program.
Funding Information:
This work was supported by the Foundation for the National Institutes of Health (NIH) (HL118268 [to D.L.K.]). T.A.W. is the recipient of a U.S. Department of Veterans Affairs Research Career Scientist Award (IK6 BX003781). The University of Nebraska Medical Center Flow Cytometry Research Facility is administrated through the Office of the Vice Chancellor for Research and supported by state funds from the Nebraska Research Initiative and The Fred and Pamela Buffett Cancer Center’s National Cancer Institute Cancer Support Grant. Major instrumentation has been provided by the Office of the Vice Chancellor for
Publisher Copyright:
© 2021 by The American Association of Immunologists, Inc.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Znmediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.
AB - Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Znmediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.
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U2 - 10.4049/jimmunol.2001395
DO - 10.4049/jimmunol.2001395
M3 - Article
C2 - 34380651
AN - SCOPUS:85113760901
SN - 0022-1767
VL - 207
SP - 1357
EP - 1370
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -