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Modeling Dysplastic and Functional Lung Alveolar Repair after Influenza Infection
Published on: September 19, 2025
CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology
Kaifeng Lisa Lin1, Yasushi Suzuki, Hideki Nakano
1Department of Medicine, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Infection with pathogenic influenza virus induces severe pulmonary immune pathology, but the specific cell types that cause this have not been determined. We characterized inflammatory cell types in mice that overexpress MCP-1 (CCL2) in the lungs, then examined those cells during influenza infection of wild-type (WT) mice. Lungs of both naive surfactant protein C-MCP mice and influenza-infected WT mice contain increased numbers of CCR2(+) monocytes, monocyte-derived DC (moDC), and exudate macrophages (exMACs). Adoptively transferred Gr-1(+) monocytes give rise to both moDC and exMACs in influenza-infected lungs. MoDC, the most common inflammatory cell type in infected lungs, induce robust naive T cell proliferation and produce NO synthase 2 (NOS2), whereas exMACs produce high levels of TNF-alpha and NOS2 and stimulate the proliferation of memory T cells. Relative to WT mice, influenza-infected CCR2-deficient mice display marked reductions in the accumulation of monocyte-derived inflammatory cells, cells producing NOS2, the expression of costimulatory molecules, markers of lung injury, weight loss, and mortality. We conclude that CCR2(+) monocyte-derived cells are the predominant cause of immune pathology during influenza infection and that such pathology is markedly abrogated in the absence of CCR2.
Insights
Influenza infection causes lung damage primarily through CCR2(+) monocyte-derived cells. Blocking this pathway significantly reduces immune pathology and mortality during influenza virus infection.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Influenza virus infection leads to severe lung immune pathology.
- The specific inflammatory cells responsible for this pathology remain unclear.
Purpose of the Study:
- To identify the key inflammatory cell types driving lung pathology during influenza infection.
- To investigate the role of CCR2(+) monocytes in mediating influenza-induced immune responses and pathology.
Main Methods:
- Characterization of inflammatory cells in mice overexpressing MCP-1 (CCL2) and in wild-type (WT) mice infected with influenza.
- Adoptive transfer of Gr-1(+) monocytes to track their differentiation into monocyte-derived dendritic cells (moDC) and exudate macrophages (exMACs).
- Analysis of influenza-infected CCR2-deficient mice compared to WT mice.
Main Results:
- Increased numbers of CCR2(+) monocytes, moDC, and exMACs were observed in the lungs of both naive MCP-1 overexpressing mice and infected WT mice.
- MoDC were the most abundant inflammatory cells, inducing naive T cell proliferation and producing NOS2.
- ExMACs produced TNF-alpha and NOS2, stimulating memory T cell proliferation.
- CCR2-deficient mice showed significantly reduced inflammatory cell accumulation, NOS2 production, costimulatory molecule expression, lung injury, weight loss, and mortality.
Conclusions:
- CCR2(+) monocyte-derived cells are the primary drivers of immune pathology during influenza infection.
- The absence of CCR2 markedly abrogates influenza-induced lung pathology and reduces mortality.
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