NOD2 Agonism Counter-Regulates Human Type 2 T Cell Functions in Peripheral Blood Mononuclear Cell Cultures: Implications for Atopic Dermatitis.
Vladimir-Andrey Gimenez-RiveraHarshita PatelFranck P DupuyZoulfia AllakhverdiCharlie BouchardJoaquín MadrenasRobert BissonnetteCiriaco A PiccirilloCarolyn JackPublished in: Biomolecules (2023)
Atopic dermatitis (AD) is known as a skin disease; however, T cell immunopathology found in blood is associated with its severity. Skin Staphylococcus aureus ( S. aureus ) and associated host-pathogen dynamics are important to chronic T helper 2 (Th2)-dominated inflammation in AD, yet they remain poorly understood. This study sought to investigate the effects of S. aureus -derived molecules and skin alarmins on human peripheral blood mononuclear cells, specifically testing Th2-type cells, cytokines, and chemokines known to be associated with AD. We first show that six significantly elevated Th2-related chemokine biomarkers distinguish blood from adult AD patients compared to healthy controls ex vivo; in addition, TARC/CCL17, LDH, and PDGF-AA/AB correlated significantly with disease severity. We then demonstrate that these robust AD-associated biomarkers, as well as associated type 2 T cell functions, are readily reproduced from healthy blood mononuclear cells exposed to the alarmin TSLP and the S. aureus superantigen SEB in a human in vitro model, including IL-13, IL-5, and TARC secretion as well as OX-40-expressing activated memory T cells. We further show that the agonism of nucleotide-binding oligomerization domain-containing protein (NOD)2 inhibits this IL-13 secretion and memory Th2 and Tc2 cell functional activation while inducing significantly increased pSTAT3 and IL-6, both critical for Th17 cell responses. These findings identify NOD2 as a potential regulator of type 2 immune responses in humans and highlight its role as an endogenous inhibitor of pathogenic IL-13 that may open avenues for its therapeutic targeting in AD.
Keyphrases
- peripheral blood
- endothelial cells
- atopic dermatitis
- induced apoptosis
- single cell
- staphylococcus aureus
- immune response
- induced pluripotent stem cells
- cell therapy
- cell cycle arrest
- pluripotent stem cells
- working memory
- end stage renal disease
- soft tissue
- oxidative stress
- ejection fraction
- dendritic cells
- transcription factor
- minimally invasive
- bone marrow
- wound healing
- chronic kidney disease
- cell death
- endoplasmic reticulum stress
- binding protein
- cystic fibrosis
- escherichia coli
- toll like receptor
- innate immune
- signaling pathway
- liver injury
- smooth muscle
- drug induced
- cancer therapy