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Exploring the development of endotoxin tolerance during sepsis and a possible immunomodulatory therapy

University of British Columbia

The immune system responds to bacterial infections by inducing pro-inflammatory mediators, which recruit and activate immune cells to eliminate the invading microbe. However, a systemic and uncontrolled inflammatory reaction may lead to the development of sepsis, which is characterized by organ failure and eventually death. Classical (M1) and alternative (M2) macrophage polarization is known to occur in response to challenges within a microenvironment, like the encounter of a pathogen. Bacterial products like lipopolysaccharide (LPS), can be a potent inducer of inflammation and M1 polarization. LPS can also generate an effect in mononuclear cells known as endotoxin tolerance, defined as the reduced capacity of a cell to respond to LPS activation after an initial exposure to this stimulus. Using systems biology approaches in PBMCs, and macrophages, it was determined here that gene responses during endotoxin tolerance were similar to those found during M2 polarization, including reduced production of proinflammatory mediators, expression of genes involved in phagocytosis, control of oxidative stress, as well as tissue remodelling (Chapter 2). Moreover, an extensive bioinformatic meta-analysis was performed using these findings, characterizing unique LPS and endotoxin tolerance gene signatures. These signatures were compared with transcriptional changes observed in human sepsis cohorts based on our data or from the literature. Very interestingly, it was found that septic patients strongly presented an immunological profile associated with an endotoxin tolerance gene signature, rather than a dominant pro-inflammatory response as commonly believed to occur in early sepsis (Chapter 3). Additionally, a potential immunomodulator for use in infections and sepsis was investigated at the mechanistic level. Here, the effect of synthetic innate defense regulator peptide (IDR1018) on macrophage differentiation was tested. The results obtained suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection (Chapter 4). In conclusion, the unique endotoxin tolerance gene signature discovered here and found in septic patients, can be used as biomarkers, that allow characterization of the critical immunological status of the septic patient, enabling the application of appropriate immunological therapies that might improve the survival rate during this deadly syndrome.

Text

2014-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/45034

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/