Nasal Streptococcus pyogenes Infection Exacerbates Psoriasiform Relapse in Mice Through TLR2-Dependent Dendritic Cell
Lijiaming Zhou1,2, Zhengchun Wang1, Jingxia Zhao1
1Department of Dermatology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, Beijing, People's Republic of China.
Background:
Nasal Streptococcus pyogenes (SP) infection triggers psoriasis relapse, with the systemic-to-cutaneous immune relay poorly understood. This study aims to elucidate role of dendritic cell (DC) metabolic reprogramming and trafficking in driving SP-induced psoriasis relapse.
Methods:
A murine psoriasis model was established using imiquimod (IMQ) and intranasal SP challenge, with disease severity evaluated via PASI scoring and histology, epidermal proliferation (Ki67) and T cell (CD3) via immunofluorescence, immunohistochemistry, and IL-23, IL-17A, and IL-1β levels via enzyme-linked immunosorbent assay (ELISA) in skin. Immune cell infiltration (DCs, γδ T cells) was analyzed by flow cytometry, RNA-seq identified affected genes and pathways, and real-time polymerase chain reaction (qPCR) /Western blot (WB) detected transcription and protein levels of target genes in SP lipoteichoic acid (LTA)-activated BMDCs in vitro. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), wound healing, Transwell migration, and co-culture assays assessed metabolic reprogramming and migration function of BMDCs in response to LTA in vitro. CD11c-Luc reporter mice were monitored via bioluminescence imaging (BLI) to dynamically track DC migration in vivo, and confocal immunofluorescence co-localization was used to visualize DC-γδT cell interactions in skin.
Results:
Nasal SP infection exacerbated psoriasis-like lesions by increasing PASI scores (10.3 ± 0.2 in Re-SP vs 8.2 ± 0.4 in Re, P < 0.01), epidermal thickness, pro-inflammatory cytokines (IL-17A levels increased by approximately 2.1-fold in Re-SP compared to Re), and promoting DC maturation, γδT cell infiltration, and IL-17A production via TLR2/NF-κB/nitric oxide synthase 2(NOS2) signaling. RNA-seq and in vitro assays demonstrated SP induces DC aerobic glycolysis (as evidenced by significantly increased ECAR and suppressed OCR) and hyper-mobility through TLR2 activation, upregulating TLR2, NF-κB markers (p-IKBα, p-p65), NOS2, and myosin-related proteins (p-myosin phosphatase target subunit 1, MYPT1 and p-myosin light chain, MLC), with inhibited TLR2 reducing these effects. In vivo, SP triggered rapid DC activation and trafficking to skin, forming immunological synapse with γδT cells to induce IL-17A.
Conclusion:
These findings suggest that nasal SP infection may exacerbate psoriasis relapse through TLR2-dependent DC metabolic reprogramming and trafficking, which in turn promote γδ T cell IL-17A production. However, as these findings are derived from preclinical mouse models and in vitro experiments, validation in human psoriasis cohorts and chronic disease models is required before clinical translation can be considered.
Insights
Nasal Streptococcus pyogenes infection worsens psoriasis by reprogramming dendritic cells. These cells migrate to the skin, promoting IL-17A production and disease relapse via TLR2 signaling.
Area of Science:
- Immunology
- Dermatology
- Metabolic pathways
Background:
- Nasal Streptococcus pyogenes (SP) infection is linked to psoriasis relapse.
- The immune mechanisms connecting systemic infection to cutaneous disease are not fully understood.
- Dendritic cell (DC) reprogramming and migration are investigated as key players.
Purpose of the Study:
- To elucidate the role of dendritic cell (DC) metabolic reprogramming and trafficking in SP-induced psoriasis relapse.
- To understand the systemic-to-cutaneous immune relay in psoriasis.
Main Methods:
- A murine psoriasis model was induced by imiquimod (IMQ) and intranasal SP challenge.
- Disease severity, immune cell infiltration, cytokine levels, and DC function (metabolism, migration) were assessed.
- RNA-sequencing, qPCR, Western blot, flow cytometry, and bioluminescence imaging were employed.
Main Results:
- Nasal SP infection aggravated psoriasis-like lesions, increasing PASI scores and IL-17A levels.
- SP induced DC aerobic glycolysis and hyper-mobility via TLR2/NF-κB/NOS2 signaling.
- DCs trafficked to the skin, forming synapses with γδ T cells to promote IL-17A production.
Conclusions:
- Nasal SP infection exacerbates psoriasis relapse through TLR2-dependent DC metabolic reprogramming and trafficking.
- This process promotes γδ T cell IL-17A production, driving disease.
- Further validation in human cohorts is needed for clinical translation.
