Lipopolysaccharide suppresses IgE‐mast cell‐mediated reactions

Abstract

Background Clinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis. Objective We examined the effect of LPS exposure on the induction of IgE-mast cell-(MC) mediated reactions in mice. Methods C57BL/6 WT, TLR-4−/− and IL10−/− mice were exposed to LPS and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+-mobilization and expression of FcεRI on peritoneal MCs were quantitated. Results We show that LPS exposure of C57BL/6 WT mice constrains IgE-MC mediated reactions. LPS-induced suppression of IgE-MC mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS-induced desensitization of MCs was short-term with MC sensitivity to IgE reconstituted within 48 hours which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcεRI surface expression. Conclusions & Clinical Relevance Collectively, these studies suggest that LPS-induced IL-10 promotes the down regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10-pathway maybe used as a therapeutic approach to prevent adverse IgE-mediated reactions.

Non‐IgE mediated mast cell activation

“…In both species, TLR4 engagement also potentiates heterologous receptor engagement effects such as FcεRI . However, in vivo in mice, LPS injection also increases IL‐10 systemically diminishing FcεRI expression on MCs, thereby desensitizing them to subsequent anti‐IgE treatment and limiting their degranulation ability and the extent of anaphylaxis . This phenomenon demonstrated in mice was induced only by LPS .…”

“…However, in vivo in mice, LPS injection also increases IL‐10 systemically diminishing FcεRI expression on MCs, thereby desensitizing them to subsequent anti‐IgE treatment and limiting their degranulation ability and the extent of anaphylaxis . This phenomenon demonstrated in mice was induced only by LPS . As in anaphylaxis worsening of symptoms in patients upon in infection is frequently observed, other PAMPs and other PRRs than LPS may also participate in this effect .…”

“…44 This phenomenon demonstrated in mice was induced only by LPS. 57 As in anaphylaxis worsening of symptoms in patients upon in infection is frequently observed, other PAMPs and other PRRs than LPS may also participate in this effect. 58 Conversely, LPS intranasal exposure along with an OVA-induced asthma model clearly leads to a BLT2-dependent increase in IL-13 production by MCs worsening the histological outcome of the protocol, as it was demonstrated in vitro in parallel.…”

FcεRI-HDAC3-MCP1 Signaling Axis Promotes Passive Anaphylaxis Mediated by Cellular Interactions

“…However, IgE is found at a much higher level in patients with various allergic diseases. Allergen-specific IgE mediates active anaphylaxis and passive anaphylaxis, such as PCA and PSA [18,19,20,21]. Lactic acid (LA) abundant in inflamed tissues can suppress IgE-mediated hypothermia in mice undergoing PSA [22].…”

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

“…For example, TLR-2 activation led to the production of TNF, IL-6, IL-13, IL-4, and IL-5, while TLR-4 induced TNF, IL-6, IL-13, and IL-1b ( 88 ). Interestingly, pre-exposure to TLR ligands suppressed IgE-induced mast cell responses in two mouse models, possibly by transiently reducing FcεRI expression ( 89 , 90 ). By contrast, simultaneous exposure of human mast cells to various TLR ligands and FcεRI stimulation yielded increased cytokine secretion without altering degranulation ( 91 ).…”