A Study of Cecal Ligation and Puncture-Induced Sepsis in Tissue-Specific Tumor Necrosis Factor Receptor 1-Deficient Mice

Abstract

Sepsis is a complex syndrome resulting from a dysregulated immune response to an infection. Due to the high prevalence, morbidity, and mortality, there is a lot of interest in understanding pathways that play a role in sepsis, with a focus on the immune system. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine and a master regulator of the immune system but clinical trials with TNF blockers in sepsis have failed to demonstrate significant protection. Since TNF stimulates two different receptors, TNF receptor 1 (TNFR1) and TNFR2, pan-TNF inhibition might be suboptimal since both receptors have opposite functions in polymicrobial sepsis. Therefore, we hypothesized that TNF has a dual role in sepsis, namely a mediating and a protective role, and that protection might be obtained by TNFR1-specific inhibition. We here confirmed that TNFR1−/− mice are protected in the sterile endotoxemia model, whereas TNFR1 deficiency did not protect in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. Since whole body TNFR1 blockage might be deleterious because of the antibacterial function of TNF/TNFR1 signaling, we focused on the potential devastating role of TNF/TNFR1 signaling in specific cell types. We were interested in the gut epithelium, the endothelium, and hepatocytes using conditional TNFR1−/− mice, as these cell types have been shown to play a role in sepsis. However, none of these conditional knockout mice showed improved survival in the CLP model. We conclude that cell-specific targeting of TNFR1 to these cell types has no therapeutic future in septic peritonitis.

A Kinetic Response Model for Standardized Regression Analyses of Inflammation-Triggered Hypothermic Body Temperature-Time Courses in Mice

“…Therefore, the mathematical model might be reliably equipped to analyze body temperature curves following systemic application of other sterile PAMPs or DAMPs as well. Furthermore, temperature-time curves obtained from murine models of bacterial septic or anaphylactic shock are also comparable to those obtained from sterile endotoxin shock (Hox et al, 2016;Li et al, 2018;Vandewalle et al, 2019). However, shock models using viable bacteria might additionally lead to prolonged inflammation and late death of animals despite regaining normal body temperature.…”

The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains

“…In general, it is known that the TNF-dependent NF-B signaling pathway contributes to LPSinduced septic shock by promoting pro-inflammatory cytokine induction (Mandal et al, 2018;Vandewalle et al, 2019). When the NF-B pathway is blocked, target cytokine induction in vivo is reduced, immune responses are suppressed, and mice are more resistant to TNF-and LPS-induced shock (Sheehan, Ruddle and Schreiber, 1989;Marino et al, 1997;Tortola et al, 2016;Mandal et al, 2018;Vandewalle et al, 2019) . In the case of Hoil-1l nzf*/nzf* mice, LPS-induced and TNF-induced shock were both milder than control mice, consistent with their reduced TNF-induced NF-B target gene expression.…”

“…To further address the role of the HOIL-1L NZF domain in immune responses, we examined LPS-induced septic shock, which is largely dependent on the TNF signaling pathway (Mandal et al, 2018;Vandewalle et al, 2019). Intriguingly, Hoil-1l nzf*/nzf* mice survived longer than wild type littermates after LPS-induced septic shock (Figure 4A), despite similarly sharp drops in temperature (Figure 4B), similar levels of infiltrating myeloid cells in the peritoneal cavity (Supplementary Figure 3A-D), and similar serum levels of the pro-inflammatory cytokines, IL-6, IL-27 and G-CSF (Figure 4D-F).…”

Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects

“…However, the importance of TNFR2 in wound repair may confound any infection-control conclusions of this surgical model. Meanwhile, LPS mediated effects on infection and inflammation appear to operate through TNFR1 ( 91 – 93 ), while off target effects of inflammation (such as allergic sensitization and Chlamydia induced atherosclerosis) were mediated by TNFR2 ( 96 , 97 ). Both allergic rhinitis-associated and neurogenic olfactory dysfunction are mediated by TNFR1 ( 95 ).…”