NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

Abstract

The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD. Cellular & Molecular Immunology

Aberrant Expression of Bacterial Pattern Recognition Receptor NOD2 of Basophils and Microbicidal Peptides in Atopic Dermatitis

“…S. aureus can exacerbate or contribute to persistent skin inflammation in AD by secreting toxins with superantigenic properties, resulting in marked activation of T cells and other immune cells [8]. Toll-like receptors (TLR), a group of innate immunity-related pattern recognition receptors (PRR) that mediated the activation of eosinophils and dermal fibroblasts cells in allergic inflammation, have been extensively studied [9,10,11]. Cell surface TLR2 on keratinocytes recognizing bacterial cell wall component peptidoglycan (PGN) of S. aureus contributes to the innate immune response via intracellular signaling transduction [12,13].…”

Cellular and molecular regulation of innate inflammatory responses

“…NOD1 and NOD2 agonists play synergistic effects with TLR2, TLR3, TLR4, and TLR9 agonists to promote maturation and activation of DCs and basophils. [101][102][103] On the contrary, NOD2 deficiency increases TLR2-mediated activation of NF-κB and dysregulated TLR2 in NOD2-deficient mice causes the development of antigenspecific colitis. 104,105 Not only NOD2, many other NLRs play inhibitory roles in regulating the signaling of TLRs: for NLRX1 and NLRC3 via interfering with the TRAF6-NF-κB signaling; 61,106,107 for NLRC5 via interacting with and blocking phosphorylation of IκB kinase α (IKKα) and IKKβ; 59 for NRLP6 and NLRP12 via targeting MAPK and NF-κB activation; 108,109 for NLRC4 via downregulating TLR5-mediated antibody immune responses against flagellin.…”

IgE Autoreactivity in Atopic Dermatitis: Paving the Road for Autoimmune Diseases?

“…Indeed, S. aureus and other bacteria found on the skin of AD patients (such as Roseomonas mucosa) induce a skin barrier dysfunction and an IgE secretion after inoculation on the skin of rodent AD models, while a healthy microbiome is protective [ 23 , 24 ]. Furthermore, S. aureus products alone can induce an epidermal barrier dysfunction and skin inflammation, the development of specific IgE, skin mast cell activation, and eosinophils and basophils recruitment, which supports the fact that S. aureus colonization is an integrant part of the AD pathogenesis [ 25 , 26 ].…”