Airway Activation of Formyl Peptide Receptors Inhibits Th1 and Th17 Cell Responses via Inhibition of Mediator Release from Immune and Inflammatory Cells and Maturation of Dendritic Cells

Abstract

Formyl peptide receptors (FPRs) are chemoattractant receptors that mediate inflammatory cell responses to infection. Recent evidence indicates that noneosinophilic asthma phenotypes can be developed by both Th1 and Th17 cell responses when exposed to LPS-containing allergens. In this study, we evaluated the effects of airway activation of FPRs by their synthetic agonist, Trp-Lys-Tyr-Met-Val-D-Met (W-peptide), on the development of Th1 and Th17 cell responses in a noneosinophilic asthma mouse model. A noneosinophilic asthma mouse model was generated by intranasal sensitization with 10 μg of LPS plus 75 μg of OVA on days 0, 1, 2, and 7. Mice were then challenged with 50 μg of OVA alone on days 14, 15, 21, and 22. W-peptide was administered during the sensitization period, and immune and inflammatory responses were evaluated after OVA challenge. Lung inflammation after OVA challenge was partly abolished by airway activation of FPRs during sensitization. Maturation of dendritic cells (DCs) and migration of DCs from the lung to lung-draining lymph nodes were inhibited by FPR activation. In addition, airway activation of FPRs inhibited allergen-specific T cell proliferation in the lymph nodes. Production of IL-12 and IL-6 (Th1- and Th17-polarizing cytokines) from lung DCs was decreased by airway activation of FPRs. This effect resulted in the inhibition of allergen-specific Th1 and Th17 cell responses. Airway activation of FPRs during sensitization effectively prevents the development of Th1 and Th17 cell responses induced by LPS-containing allergens via multiple mechanisms, such as inhibition of DC maturation and migration and the production of Th1- and Th7-polarizing cytokines.

Staphylococcus aureus Phenol-Soluble Modulin Peptides Modulate Dendritic Cell Functions and Increase In Vitro Priming of Regulatory T Cells

“…PSMs did not affect priming of Th17 cells, although secretion of the Th17-inducing cytokine IL-6 by DCs was reduced. This is in contrast to data from a non-eosinophilic asthma mouse model showing that activation of FPRs by a synthetic W-peptide inhibits both Th17 and Th1 responses by modulating airway DCs (52). This difference might be explained by the different TLR stimuli used or that our in vitro system lacks certain characteristics of an in vivo system, which might influence priming of Th17 cells.…”

Heme Oxygenase-1 Exerts a Protective Role in Ovalbumin-induced Neutrophilic Airway Inflammation by Inhibiting Th17 Cell-mediated Immune Response

“…Therefore, this is generally considered to be a useful model for the investigation of antigen-induced Th17-mediated neutrophilic airway inflammation (22,23,36,37). In the current study, we observed that OVA challenge resulted in an increased number of macrophages in BALF, consistent with findings reported by Nakagome et al (37) and Tae et al (38). The results indicate that the increased neutrophil response in mice with OVA-induced airway inflammation is accompanied by an increased number of macrophages.…”

Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation

“…Myelin-specific T-cells in NF-κB1 (p50)-deficient mice are deficient in differentiating into either Th1 or Th2 cells [17]. This concept was further refined by Dasgupta and co-workers who showed positive effects of NF-κB on the differentiation of myelin-specific Th1 cells, but a negative influence on the differentiation into Th2 cells [19]. In line with these observations, severely impaired T-cell responses were found in immune cell cultures derived from mice with a T-cell specific deficiency in IKK2, a pivotal kinase for NF-κB activation (IKK2 Δ T-cell mice) [20].…”