Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide

Abstract

Background Mast cells are indispensible for LPS-induced septic hypothermia, in which TNF-α plays an essential role to initiate septic responses. ITK and BTK regulate mast cell responses to allergen, but their roles in mast cell responses in LPS-induced sepsis are unclear. Objectives We sought to investigate the roles of ITK and BTK in mast cell responses during LPS-induced septic inflammation. Methods Mice (genetically modified or BMMC-reconstituted Sash) were given LPS to induce septic hypothermia, in the presence or absence of indicated inhibitors. Flow cytometry was used to determine LPS-induced cell influx and TNF-α production in peritoneal cells. Microarray was used for genome-wide gene expression analysis on BMMCs. Quantitative PCR and multiplex were used to determine transcribed and secreted pro-inflammatory cytokines. Microscopy and western blotting were used to determine activation of signal transduction pathways. Results The absence of ITK and BTK leads to exacerbation of LPS-induced septic hypothermia and neutrophil influx. Itk−/−Btk−/− mast cells exhibit hyperactive preformed and LPS-induced TNF-α production, and lead to more severe LPS-induced septic hypothermia when reconstituted into mast cell deficient Sash mice. LPS-induced NF-κB, Akt and p38 activation is enhanced in Itk−/−Btk−/− mast cells, and blockage of PI3K, Akt or p38 downstream MNK1 activation significantly suppresses TNF-α hyper-production and attenuates septic hypothermia. Conclusions ITK and BTK regulate thermal homeostasis during septic response through mast cell function in mice. They share regulatory function downstream of TLR4/LPS in mast cells, through regulating the activation of canonical NF-κB, PI3K/Akt and p38 signaling pathways.

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

“…The redistribution of Mtb in different phagocytes in the absence of ITK appears to correlate with the increased bacterial burden in the lung 4 weeks postinfection. Other than T cells, ITK has been indicated to regulate functions of innate immune cells such as mast cells (77,78). However, potential intrinsic functions of ITK in lung macrophages and neutrophils during Mtb infection would merit further studies.…”

Effect of scaling and root planing on level of immunoglobulin E and immunoglobulin G4in children with gingivitis and house-dust mite allergy: A pilot randomised controlled trial

“…This reduces the subject body's load of LPS-triggered mast cells derived from periodontal inflammation. 49,50 Following dental SRP, there is also evidence of increasing certain Lactobacilli populations, which are beneficial for controlling atopic inflammatory pathway. 51 It is widely accepted that Lactobacilli in the oral cavity may determine the population of Lactobacilli in the gut.…”

Correlation between Salivary Lipopolysaccharide ofPorphyromonas gingivaliswith Circulatory Immunoglobulin-E and Immunoglobulin-G4in Periodontally Healthy Children with House Dust Mite Allergy

“…Since SOCS3 is an inducible endogenous negative regulator of JAK/STAT pathway [34], therefore administration of lipopolysaccharide in a model of experimental periodontal disease will be correlated with dynamics of the atopic inflammatory reaction [35]. Meanwhile, given the unique lipopolysaccharide-induced atopic inflammatory responses and lipopolysaccharide-triggered mast cell derived, we can predict that lipopolysaccharide of this periodontal pathogen may stimulate the level of circulatory Ig-E and Ig-G 4 , even in the healthy populations [36,37].…”