Tyk2 in the innate immune response during sepsis

Sepsis is a systemic inflammatory reaction initiated by the presence of bacteria, or their products (e.g. endotoxins), in the bloodstream and may lead to septic shock and multi-organ failure. The pathogenesis is incompletely understood and sepsis still represents a major problem in health care due to high mortality rates. Absence of Tyk2 in mice results in an increased resistance against lipopolysaccharide (LPS)-induced endotoxin shock, an experimental model for severe sepsis. Tyk2 belongs to the Janus kinase family of receptor-associated tyrosine kinases and is an integral part of signalling cascades initiated by multiple cytokines. Most of the Tyk2-utilizing cytokines are involved in the regulation of innate and/or adaptive immune responses, although with often opposing functions. It is currently unclear how Tyk2 contributes to the development of endotoxin shock and little is known about its role in sepsis induced by live bacteria. The proposed project is based on the availability of newly generated gene-modified mice, including knockin mice expressing kinase-inactive Tyk2 and conditional Tyk2 knockout mice. This will for the first time allow the study of whether kinase-inactivation of Tyk2 suffices to protect from LPS-induced endotoxin shock and will enable us to assess the contribution of Tyk2 in distinct cell populations to immune responses during sepsis. Within the proposed project we aim to further characterize Tyk2 functions during endotoxemia and to extend these studies to an experimental model of sepsis induced by live bacteria. The results generated will help us to understand the complex network of signalling cascades involved in the pathogenesis of sepsis and may contribute to the design of new therapeutic strategies.

The project aimed at a better understanding of how tyrosine kinase 2 (TYK2) orchestrates immune responses during sepsis. Sepsis is a systemic inflammatory reaction initiated by the presence of bacteria, or their products (e.g. lipopolysaccharide, LPS), in the bloodstream and may lead to septic shock and multi-organ failure. The pathogenesis is incompletely understood and sepsis still represents a major problem in intenisve care units. While it is known for some time that TYK2 promotes LPS-induced inflammation, underlying mechanisms and its role during bacterially induced sepsis remained largely unclear. TYK2 is a signal-transducing kinase that is activated by a number of cytokines with crucial immune regulatory activities. Focus of our study was on characterizing how TYK2 contributes to disease progression and on the question whether TYK2 kinase-inactivation suffices to protect from endotoxin-induced inflammation and sepsis caused by infection with live Escherichia coli bacteria. We found that TYK2 does not affect the onset of disease but aggravates inflammation at later times. We could show that TYK2 facilitates the upregulation of a critical component of the non-canonical inflammasome, which senses intracellular LPS and results in processing and secretion of the pro-inflammatory cytokines interleukin- (IL-) 1? and IL-18. We could identify myeloid cells as the main cell populations involved in the TYK2-dependent late production of these cytokines. We furthermore found that both the absence of TYK2 or the presence of kinase-inactive TYK2 increased survival in a bacterial sepsis model, although the benefit was less pronounced than during sterile inflammation. Our project furthermore contributed to the finding that TYK2-dependent production of IL-27 is involved in the pathogenesis of sterile and polymicrobial sepsis. In contrast, we found an unanticipated role for TYK2 for the protection from liver damage and the production of the hepatoprotective cytokine IL-22. Results generated contributed to a better understanding of molecular mechanisms that drive the pathophysiology of sepsis and might help in the design of new therapeutic strategies for the treatment of hyperinflammatory diseases.