TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism

Abstract

Histamine is a bioactive amine that exerts immunomodulatory functions, including many allergic symptoms. It is preformed and stored in mast cells and basophils but recent evidence suggests that other cell types produce histamine in an inducible fashion. During infection, it has been suggested that neutrophils may produce histamine. We also observed that histamine is released in a neutrophil-mediated LPS-induced model of acute lung injury. Therefore, we sought to examine whether innate signals promote histamine production by neutrophils. Bone marrow-derived neutrophils stimulated with a range of TLR agonists secreted histamine in response to LPS or R837, suggesting TLR4 or TLR7 are important. LPS-driven histamine was enhanced by coculture with GM-CSF and led to a transient release of histamine that peaked at 8 hours post stimulation. This was dependent upon de novo synthesis of histamine, since cells derived from histidine decarboxylase (HDC) deficient mice were unable to produce histamine but did generate reactive oxygen species upon stimulation. Using pharmacological inhibitors, we show that histamine production requires PI3 kinase, which has been shown to regulate other neutrophil functions, including activation and selective granule release. However, unlike mast cells, HDC deficiency did not alter the granule structure of neutrophils, suggesting that histamine does not participate in granule integrity in these cells. Consequently, our findings establish that neutrophils generate histamine in response to a select panel of innate immune triggers and that this might contribute to acute lung injury responses.

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…In these models, histamine deficiency accelerates neutrophil and macrophage accumulation into dermis and peritoneum, respectively, indicating an antiinflammatory effect of histamine, which can be attributed to the functional expression of H 2 R in these cells (Hasturk et al, 2006;Cho et al, 2011;Reher et al, 2012a). Neutrophils and mast cells also produce histamine upon proper stimulation [i.e., activation of Toll-like receptor 4 (TLR4) or TLR7], in a phosphatidylinositol 3-kinase-dependent manner (Smuda et al, 2011). In contrast to mast cells, neutrophils do not store histamine in granules, and histamine is not necessary for granule integrity.…”

Allergen endotoxins induce T-cell–dependent and non–IgE-mediated nasal hypersensitivity in mice

“…43 However, the present study showed that they were not involved in Ec-OVA-elicited rhinitis because DT-treated Mas-TRECK mice had a frequency of sneezing comparable to that of DT-treated WT mice. Other than these cell types, several hematopoietic cell types (macrophages, 17 neutrophils, 18 lymphocytes, 19 and platelets 20 ), as well as nonhematopoietic cells (keratinocytes 21 and fibroblasts 22 ), can produce histamine. LPS stimulation upregulates histamine production from macrophages, 17 neutrophils, 18 and keratinocytes.…”

“…Other than these cell types, several hematopoietic cell types (macrophages, 17 neutrophils, 18 lymphocytes, 19 and platelets 20 ), as well as nonhematopoietic cells (keratinocytes 21 and fibroblasts 22 ), can produce histamine. LPS stimulation upregulates histamine production from macrophages, 17 neutrophils, 18 and keratinocytes. 21 In this study, we showed that the LPS-TLR4 pathway triggered the sneezing response, and clodronate treatment specifically abrogated endotoxin-elicited, but not IgE-mediated, rhinitis.…”

“…4,16 In addition, many cell types other than mast cells/basophils can produce and release histamine by non-IgE-mediated mechanisms. [17][18][19][20][21][22] These observations prompted us to investigate the causes and mechanisms of non-IgE-mediated type-1-hypersensitivity-like reactions. LPS, also known as endotoxin, is a component of the gramnegative bacterial cell wall and is a common contaminant in several allergens including household dust [23][24][25] and animal dander, 26,27 as well as ambient air pollutants.…”

Modulation of neutrophil oxidative burst via histamine receptors

“…It has been suggested that neutrophils may also produce and release histamine during inflammatory reactions. Smuda et al (2011) observed that bone marrow-derived neutrophils stimulated with a range of toll-like receptor (TLR) agonists secreted histamine in response to LPS or compound R837, suggesting an important role for TLR4 or TLR7 in this effect. LPSstimulated histamine release was enhanced by co-culture with granulocyte-macrophage colony-stimulating factor; this release of histamine was transient and peaked 8 h after stimulation.…”