Impaired antigen-specific lymphocyte priming in mice after Toll-like receptor 4 activation via induction of monocytic myeloid-derived suppressor cells.

In sepsis, the pathology involves a shift from a proinflammatory state toward an immunosuppressive phase. We previously showed that an agonistic anti-TLR4 antibody induced long-term endotoxin tolerance and suppressed antigen-specific secondary IgG production when primed prior to immunization with antigen. These findings led us to speculate that TLR4-induced innate tolerance due to primary infection causes an immunosuppressive pathology in sepsis.

Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation.

Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood.

An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody.

Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) elicits the innate immune response and can trigger septic shock if excessive. Two antibodies (HT4 and HT52) inhibit LPS-induced human TLR4 activation via novel LPS binding-independent mechanisms. The HT52 epitope resides on leucine-rich repeat 2 (LRR2) and is a feature of many inhibitory antibodies; antigen specificity of HT4 does not reside in LRR2.

Leucine-rich repeat 2 of human Toll-like receptor 4 contains the binding site for inhibitory monoclonal antibodies.

Excessive activation of Toll-like receptor 4 (TLR4)/MD-2 by lipopolysaccharide (LPS) causes septic shock. We previously produced an inhibitory antibody, HT52, against LPS-induced human TLR4 activation independently of LPS binding of MD-2. Consistent with the hypothesis that HT52 recognizes the epitopes inherent to inhibitory antibodies, we generated an HT52-crossblockable antibody and revealed the relationship between its inhibitory activity and the anti-TLR4 antibody epitope.