Flagellin Treatment Protects against Chemicals, Bacteria, Viruses, and Radiation

Abstract

Sudden exposure of human populations to chemicals, pathogens, or radiation has the potential to result in substantial morbidity. A potential means of rapidly protecting such populations might be to activate innate host defense pathways, which can provide broad protection against a variety of insults. However, innate immune activators can, by themselves, result in severe inflammatory pathology, which in large part is driven by hemopoietic-derived cytokines such as TNF-α. We reasoned that, because it preferentially activates epithelial cells, the TLR5 agonist flagellin might not induce severe inflammatory pathology and yet be an ideal agent to provide such non-specific protection, particularly at the mucosal surfaces that serve as a front line of host defense. In accordance, we observed that systemic treatment of mice with purified flagellin did not induce the serologic, histopathologic, and clinical hallmarks of inflammation that are induced by LPS but yet protected mice against chemicals, pathogens, and ionizing radiation. Flagellin-elicited radioprotection required TLR5, the TLR signaling adaptor MyD88, and was effective if given between 2 h before to 4 h after exposure to irradiation. Flagellin-elicited radioprotection was, in part, mediated via effects on cells in bone marrow but yet rescued mortality without a pronounced rescue of radiation-induced anemia or leukopenia. Thus, systemic administration of flagellin may be a relatively safe means of providing temporary non-specific protection against a variety of challenges.

Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity

“…Moreover, TLR5 activation was not caused by contamination of PEI with bacterial or other protein source, as endotoxin was undetectable in the PEI preparation and PEI treated overnight with proteinase K - a procedure that completely ablates the activity of flagellin to activate TLR5 - induced the same dose-dependent TLR5 activation ( Figure 4B). In addition, intraperitoneal administration of linear PEI in WT mice, pretreated or not with proteinase K, induced the same serum cytokine secretion pattern reported for flagellin (30), with significant and selective upregulation of keratinocyte chemoattractant (KC) and IFN-inducible protein 10 (IP-10) 2 hours after injection ( Figure 4C and Supplemental Figure 4B). Most importantly, PEI-mediated KC and IP-10 upregulation was completely abrogated in Tlr5 -/-littermates ( Figure 4C), confirming that linear PEI is a TLR5 agonist, which we believe to be novel, with a range of activities similar to those of flagellin.…”

TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa

“…Flagellin-mediated protection of rodents and nonhuman primates against lethal irradiation was associated with CSF3-mediated granulopoiesis and the antiapoptotic effect of superoxide dismutase 2 (47). Flagellin treatment has been linked to resistance against inflammatory colitis and gut infections (40,48). The TLR5-induced circulating and local production of IL-17/IL-22 may be the main driving force behind these protective effects.…”

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

“…23 An additional study did not observe the same side effects using 25-50 mg/mouse. 16 This is one reason why we analyzed the dose-dependent effects of flagellin on the development of liver injury in mice and tested doses of 0-200 mg. The current data suggest that the gross lesions in liver and significant increase in serum ALT/AST levels usually occurred 12 h after the intraperitoneal treatment with 100 or 200 mg, but not with lower doses.…”

“…15 Furthermore, flagellin has the potential to be used as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. 6 Vijay-Kumar et al 16 demonstrated that the systemic administration of flagellin might be a relatively safe means of providing temporary nonspecific protection against chemical, bacterial, viral and radiation challenge. However, in contrast, several studies have shown that flagellin not only triggers a prototypical systemic inflammatory response in mice, including the induction and secretion of pro-inflammatory cytokines in the lungs, small intestine, liver and kidney, 17 but also plays an important pathophysiological role in certain inflammatory diseases.…”