Systemic Activation of TLR3-Dependent TRIF Signaling Confers Host Defense against Gram-Negative Bacteria in the Intestine

Abstract

Recognition of Gram-negative bacteria by toll-like receptor (TLR)4 induces MyD88 and TRIF mediated responses. We have shown that TRIF-dependent responses play an important role in intestinal defense against Gram-negative enteropathogens. In the current study, we examined underlying mechanisms of how systemic TRIF activation enhances intestinal immune defense against Gram-negative bacteria. First we confirmed that the protective effect of poly I:C against enteric infection of mice with Yersinia enterocolitica was dependent on TLR3-mediated TRIF signaling by using TLR3-deficient mice. This protection was unique in TRIF-dependent TLR signaling because systemic stimulation of mice with agonists for TLR2 (Pam3CSK4) or TLR5 (flagellin) did not reduce mortality on Y. enterocolitica infection. Systemic administration of poly I:C mobilized CD11c+, F4/80+, and Gr−1hi cells from lamina propria and activated NK cells in the mesenteric lymph nodes (MLN) within 24 h. This innate immune cell rearrangement was type I IFN dependent and mediated through upregulation of TLR4 followed by CCR7 expression in these innate immune cells found in the intestinal mucosa. Poly I:C induced IFN-γ expression by NK cells in the MLN, which was mediated through type I IFNs and IL-12p40 from antigen presenting cells and consequent activation of STAT1 and STAT4 in NK cells. This formation of innate immunity significantly contributed to the elimination of bacteria in the MLN. Our results demonstrated an innate immune network in the intestine that can be established by systemic stimulation of TRIF, which provides a strong host defense against Gram-negative pathogens. The mechanism underlying TRIF-mediated protective immunity may be useful to develop novel therapies for enteric bacterial infection.

Pre-treatment with the viral Toll-like receptor 3 agonist poly(I:C) modulates innate immunity and protects neutropenic mice infected intracerebrally with Escherichia coli

“…In murine Yersinia enterocolitica infection, systemic administration of poly(I:C) activated NK cells in the mesenteric lymph nodes and induced their IFN-γ expression. Poly(I:C)-induced NK cell activation was mediated by type 1 IFNs and IL-12p40 [36]. In the present study, unlike other pro-inflammatory compounds, IFN-γ concentrations were not positively correlated with bacterial densities (spleen: r s = − 0.37, P = 0.07), and IFN-γ concentrations in the spleen and cerebellum remained high in surviving poly(I:C)-treated mice.…”

Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-β Synthesis Induced by Lipopolysaccharide

“…Several studies have demonstrated that TRIF-dependent IFNβ production is an important feature of the host-response that aids in the resolution of gram negative bacterial infections (55–57). However, gram negative bacteria pathogens such as Yersinia and Klebsiella have evolved an armament of virulence factors to manipulate host-responses and facilitate their pathogenesis.…”

“…Protective host defenses mediated specifically by TRIF have been described in response to several gram-negative bacterial pathogens (55–57). For instance, pulmonary infection by Klebsiella has been found to become significantly more deadly in TRIF-deficient mice (55).…”

“…For instance, pulmonary infection by Klebsiella has been found to become significantly more deadly in TRIF-deficient mice (55). Conversely, pre-administration of TLR3 agonist, poly(I:C), which engages TRIF-dependent signaling exclusively, has been shown to promote clearance of gram negative bacterial pathogens (57). Given these observations, our data raise the question as to whether previously described TRIF-dependent protective host responses are mediated by RIPK1/RIPK3 in vivo .…”

Raf Kinase Inhibitor Protein Preferentially Promotes TLR3-Triggered Signaling and Inflammation

“…T oll-like receptors are essential components of the immune system and play an important role in infectious and noninfectious disease processes. For example, TLR3 plays a protective role in enteric bacterial infection (1). Bipolar disorder patients exhibit high expression of TLR2 and TLR5 (2).…”