Badovinac, V. P. | bioRxiv Science

bioRxiv2023

Hepatic IRE1 Protects Against Septic Cardiac Failure

SUMMARYMetabolic reprogramming in response to infection plays a critical role for septic survival. During a septic episode, the heart heavily relies on hepatic lipid particles to prevent heart damage and failure. Inositol- Requiring Enzyme 1 (IRE1) is the most conserved unfolded protein response (UPR) regulator that governs homeostasis of the endoplasmic reticulum (ER), the major site for lipid synthesis and processing. Here we show that hepatocyte IRE1 is indispensable for protecting against septic mortality in two different rodent models of experimental sepsis. The protective effect of hepatic IRE1 was not attributed to the inflammatory response since hepatic IRE1 deletion did not alter hepatic or systemic cytokine response. However, loss of IRE1 in the liver significantly augmented septic cardiac dysfunction in part due to a skewed immune-metabolic balance. Lipidomic and metabolomic analyses further revealed that loss of IRE1 in the liver compromised adaptive intrahepatic and circulating lipid reprogramming, including VLDL, in response to septic challenge. Furthermore, we identified that the protective effects against septic mortality are mediated by a non-canonical IRE1-dependent mechanism. Together, our study provides the first insight into how a disruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance.

pathology↗

bioRxiv2021

Autoimmunity increases susceptibility to and mortality from sepsis

Our prior publication detailing how sepsis influences subsequent development of EAE presented a conceptual advance in understanding the post-sepsis chronic immunoparalysis state (Jensen et al., 2020). However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. Herein, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis incidence among MS, relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis well-established murine models of MS and sepsis, EAE and CLP, respectively, were utilized. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and S. pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant.

immunology↗