Innate Immune Response of Alveolar Macrophage to House Dust Mite Allergen Is Mediated through TLR2/-4 Co-Activation

Abstract

House dust mite, Dermatophagoides pteronyssinus (Der p), is one of the major allergens responsible for allergic asthma. However, the putative receptors involved in the signalization of Der p to the innate immune cells are still poorly defined as well as the impact of their activation on the outcome of the allergen-induced cell response. We previously reported that the HDM activation of mouse alveolar macrophages (AM) involves the TLR4/CD14 cell surface receptor complex. Here using a TLR ligand screening essay, we demonstrate that HDM protein extract engages the TLR2, in addition to the TLR4, in engineered TLR-transfected HEK cells but also in the MH-S mouse alveolar macrophage cell line model. Moreover we found that the concomitant recruitment of the MH-S cell’s TLR2 and TLR4 receptors by the HDM extract activates the MyD88-dependent signaling pathway and leads to the secretion of the NF-κB regulated pro-inflammatory factors NO and TNF-α. However unlike with the canonical TLR4 ligand (i.e. the bacterial LPS) mobilization of TLR4 by the HDM extract induces a reduced production of the IL-12 pro-inflammatory cytokine and fails to trigger the expression of the T-bet transcription factor. Finally we demonstrated that HDM extract down-regulates LPS induced IL-12 and T-bet expression through a TLR2 dependent mechanism. Therefore, we propose that the simultaneous engagement of the TLR2 and TLR4 receptors by the HDM extract results in a cross regulated original activation pattern of the AM which may contribute to the Th2 polarization of the allergen-induced immune response. The deciphering of these cross-regulation networks is of prime importance to open the way for original therapeutic strategies taking advantage of these receptors and their associated signaling pathways to treat allergic asthma.

Immortalized MH-S cells lack defining features of primary alveolar macrophages and do not support mouse pneumovirus replication

“…3, MH-S cells produce and release IL-6 and CXCL-10 in response to synthetic ligands for the pattern recognition receptors TLR2 and NOD2, as well as in response to challenge with heat-inactivated Gram-positive Lactobacillus reuteri. Although MH-S cells have been previously shown to express TLR2 [8], this is the first report that documents responses consistent with expression of the intracellular pattern recognition receptor NOD2. Like TLR2, NOD2 recognizes pathogen associated molecular patterns (PAMPs), which leads to transcription of NF-kB-dependent gene targets [40].…”

“…Adherent cells from bronchoalveolar lavage of BALB/cJ mice were infected with Simian Virus (SV)-40; the resulting immortalized cells expressed the surface receptors Mac-1 (CD11b/CD18) and produced IL-1 in response to lipopolysaccharide (LPS) stimulation. Recent reports on this cell line note constitutive expression of pattern recognition receptors (PRRs) toll-like receptor (TLR)2 and TLR4 [8], and the ability to phagocytose latex beads [9]. …”

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

“…critical to the development of a type-2 immune response (15)(16)(17)(18)(19)(20). Thus far, there has been little evidence implicating sPLA 2 -X as a regulator of these responses; however, a recent paper examining the effect of bee venom PLA 2 (bvPLA 2 ) in the periphery demonstrated that bvPLA 2 induces the release of IL-33, leading to the generation of ILC2s and subsequent antigen-specific T cell responses (21).…”

Zinc sulfate improved the unbalanced T cell profiles in Der p‐allergic asthma: An ex vivo study

“…Der p is known to express major IgE-binding proteins, with unknown biological functions, and exposure to Der p can increase IgE production and stimulate T cell proliferation. 6 Der p induce Th 2 cells to release interleukin (IL)-4, IL-5, and IL-13 7,8 to increase the production of inflammatory cells, including neutrophils, macrophages, mast cells, and eosinophils, as well as infiltration, cytokines (IL-6 and IL-8), smooth muscle cell proliferation, and mucus production in allergic asthma. The possible mechanism is that dendritic cells (DCs) synthesize IL-12 efficiently and are potent inducers of Th1 immune responses in healthy subjects.…”

“…5 The possible mechanisms are that Der p interact with T cell receptors (TCRs) to activate phospholipase D (PLD), which activates Th 2 cell responses. 6 Der p induce Th 2 cells to release interleukin (IL)-4, IL-5, and IL-13 7,8 to increase the production of inflammatory cells, including neutrophils, macrophages, mast cells, and eosinophils, as well as infiltration, cytokines (IL-6 and IL-8), smooth muscle cell proliferation, and mucus production in allergic asthma. These responses cause airway inflammation and remodeling, resulting in the development of asthma.…”