Cardiac Arrest Disrupts Caspase-1 and Patterns of Inflammatory Mediators Differently in Skin and Muscle Following Localized Tissue Injury in Rats: Insights from Data-Driven Modeling

Abstract

Background Trauma often cooccurs with cardiac arrest and hemorrhagic shock. Skin and muscle injuries often lead to significant inflammation in the affected tissue. The primary mechanism by which inflammation is initiated, sustained, and terminated is cytokine-mediated immune signaling, but this signaling can be altered by cardiac arrest. The complexity and context sensitivity of immune signaling in general has stymied a clear understanding of these signaling dynamics. Methodology/principal findings We hypothesized that advanced numerical and biological function analysis methods would help elucidate the inflammatory response to skin and muscle wounds in rats, both with and without concomitant shock. Based on the multiplexed analysis of inflammatory mediators, we discerned a differential interleukin (IL)-1α and IL-18 signature in skin vs. muscle, which was suggestive of inflammasome activation in the skin. Immunoblotting revealed caspase-1 activation in skin but not muscle. Notably, IL-1α and IL-18, along with caspase-1, were greatly elevated in the skin following cardiac arrest, consistent with differential inflammasome activation. Conclusion/significance Tissue-specific activation of caspase-1 and the NLRP3 inflammasome appear to be key factors in determining the type and severity of the inflammatory response to tissue injury, especially in the presence of severe shock, as suggested via data-driven modeling.

Inflammasomes in Tissue Damages and Immune Disorders After Trauma

“…Likewise, injection of necrotic cells in the peritoneum of wild-type mice leads to NLRP3 activation ( 62 ). Consistently, recent studies show the priming and activation of the NLRP3 inflammasome in the injured tissues of rodents in response to mechanical stress ( 63 , 64 ). Similar observations have been made in the brain, heart, kidney, and testis of mice exposed to hypoxia–ischemia ( 15 ).…”

“…In a rat model of acute severe stress, Maslanik et al demonstrate that caspase-1 activity promotes the production of IL-1β and IL-18 in the circulation and in peripheral tissues ( 72 ). In a mouse model of tissue contusion, Starzl et al show that NLRP3 inflammasome activation is associated with the severity of the inflammatory response through IL-1β and IL-18 secretion ( 64 ). Through multiple systemic and local effects, IL-1β is an essential actor of the inflammatory and immune response ( 73 ).…”

Inflammation Following Traumatic Brain Injury in Humans: Insights from Data-Driven and Mechanistic Models into Survival and Death

“…Thus, we hypothesize that a dynamic inflammatory network capable of mounting variable responses is a hallmark of survival. Interestingly, IL-1α is both a cytokine and a DAMP that is induced in the context of injury (Namas et al, 2015 ) that was recently inferred through modeling to be a central part of the injury response to both peripheral tissues (Starzl et al, 2015 ) and nerves (Vasudeva et al, 2015 ). Furthermore, these findings may also suggest a host-protective role for IL-1α and possibly the NLRP3 inflammasome pathway (Davis et al, 2011 ) following TBI, which should be studied further.…”

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches

“…Indeed, one commentator [ 27 ] refers to some 70% of 55 patients who died within 24 hours of head injury already exhibiting increased amyloid-β protein precursor (AβPP) in brain sections, with the earliest seen after two hours of survival. In addition, inflammasome activation occurs in all three of these conditions [ 78–80 ]. This can be expected to have induced the IL-1β, via caspase-1 activation, generated downstream from TNF.…”