Frequency of IRF5+ dendritic cells is associated with the TLR7-induced inflammatory cytokine response in SARS-CoV-2 infection. (February 2023)

• Record Type: Journal Article
• Authors: Cords, Leon; Woost, Robin; Kummer, Silke; Brehm, Thomas T.; Kluge, Stefan; Schmiedel, Stefan; Jordan, Sabine; Lohse, Ansgar W.; Altfeld, Marcus; Addo, Marylyn M.; Schulze zur Wiesch, Julian; Beisel, Claudia
• Is Part Of: Cytokine. Volume 162(2023)
• Publication Date: 2023-02
• Subjects: SARS-CoV-2 -- Dendritic cells -- Interferon regulatory factor 5 -- Toll-like receptor 7 -- Interferon-α -- Tumor necrosis factor-α -- Interleukin-6; COVID-19 Coronavirus Disease 2019 -- CRP C-reactive protein -- DC Dendritic cell -- ECMO Extracorporal membrane oxygenation -- HD Healthy donor -- ICU Intensive care unit -- IRF5 Interferon regulatory factor 5 -- IFN-α Interferon alpha -- IL-6 Interleukin 6 -- ILT-3 Immunoglobulin-like transcript 3 -- MFI Median fluorescence intensity -- mDC Myeloid Dendritic Cell -- MyD88 Myeloid differentiation primary response 88 -- PBMC Peripheral Blood Mononuclear Cell -- PCR Polymerase chain reaction -- pDC Plasmacytoid Dendritic Cell -- SARS-CoV-2 Severe acute respiratory syndrome coronavirus type 2 -- SNP single-nucleotide polymorphism -- TLR7 Toll-like receptor 7 -- TNF-α Tumor necrosis factor alpha; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2022.156109
• Languages: English
• ISSNs: 1043-4666

Abstract

Highlights: The peripheral blood dendritic cell compartment was significantly altered during SARS-CoV-2 infection. IRF5+ mDCs were significantly reduced in SARS-CoV-2 infected individuals compared with healthy donors. In response to TLR7 stimulation, mDCs of SARS-CoV-2 infected patients produced lower levels of IL-6. Our data provide insights into underlying mechanisms of TLR7-dependent immune dysfunction in COVID-19 and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection. Abstract: The SARS-CoV-2 infection leads to enhanced inflammation driven by innate immune responses. Upon TLR7 stimulation, dendritic cells (DC) mediate the production of inflammatory cytokines, and in particular of type I interferons (IFN). Especially in DCs, IRF5 is a key transcription factor that regulates pathogen-induced immune responses via activation of the MyD88-dependent TLR signaling pathway. In the current study, the frequencies of IRF5+ DCs and the association with innate cytokine responses in SARS-CoV-2 infected individuals with different disease courses were investigated. In addition to a decreased number of mDC and pDC subsets, we could show reduced relative IRF5+ frequencies in mDCs of SARS-CoV-2 infected individuals compared with healthy donors. Functionally, mDCs of COVID-19 patients produced lower levels of IL-6 in response to in vitro TLR7 stimulation. IRF5+ mDCs more frequently produced IL-6 and TNF-α compared to their IRF5− counterparts upon TLR7 ligation. The correlation of IRF5+ mDCs with the frequencies of IL-6 and TNF-α producing mDCs were indicators for a role of IRF5 in the regulation of cytokine responses in mDCs. In conclusion, our data provide further insights into the underlying mechanisms of TLR7-dependent immune dysfunction and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection.