Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis

Amel Komic, Patricia Martinez-Quinones, Cameron G. McCarthy, R. Clinton Webb, Camilla F. Wenceslau

Research output: Contribution to journalArticle

Abstract

Sepsis is a profoundly morbid and life-threatening condition, and an increasingly alarming burden on modern healthcare economies. Patients with septic shock exhibit persistent hypotension despite adequate volume resuscitation requiring pharmacological vasoconstrictors, but the molecular mechanisms of this phenomenon remain unclear. The accumulation of misfolded proteins is linked to numerous diseases, and it has been observed that soluble oligomeric protein intermediates are the primary cytotoxic species in these conditions. Oligomeric protein assemblies have been shown to bind and activate a variety of pattern recognition receptors (PRRs) including formyl peptide receptor (FPR). While inhibition of endoplasmic reticulum (ER) stress and stabilization of protein homeostasis have been promising lines of inquiry regarding sepsis therapy, little attention has been given to the potential effects that the accumulation ofmisfolded proteins may have in driving sepsis pathogenesis. Here we propose that in sepsis, there is an accumulation of toxic misfolded proteins in the form of soluble protein oligomers (SPOs) that contribute to the inflammation and vascular dysfunction observed in sepsis via the activation of one or more PRRs including FPR. Our laboratory has shown increased levels of SPOs in the heart and intrarenal arteries of septic mice. We have also observed that exposure of resistance arteries and vascular smooth muscle cells to SPOs is associated with increased mitogen-activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (p-ERK) and p-P38 MAPK pathways, and that this response is abolished with the knockout of FPR. This hypothesis has promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in sepsis.

Original languageEnglish (US)
Pages (from-to)1433-1438
Number of pages6
JournalClinical Science
Volume132
Issue number13
DOIs
StatePublished - Jul 1 2018

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Blood Vessels
Immune System
Sepsis
Inflammation
Formyl Peptide Receptor
Proteins
Pattern Recognition Receptors
Arteries
Endoplasmic Reticulum Stress
Poisons
Extracellular Signal-Regulated MAP Kinases
Vasoconstrictor Agents
p38 Mitogen-Activated Protein Kinases
Septic Shock
Heat-Shock Proteins
Mitogen-Activated Protein Kinases
Vascular Smooth Muscle
Resuscitation
Hypotension
Smooth Muscle Myocytes

ASJC Scopus subject areas

  • Medicine(all)

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Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis. / Komic, Amel; Martinez-Quinones, Patricia; McCarthy, Cameron G.; Clinton Webb, R.; Wenceslau, Camilla F.

In: Clinical Science, Vol. 132, No. 13, 01.07.2018, p. 1433-1438.

Research output: Contribution to journalArticle

Komic, Amel ; Martinez-Quinones, Patricia ; McCarthy, Cameron G. ; Clinton Webb, R. ; Wenceslau, Camilla F. / Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis. In: Clinical Science. 2018 ; Vol. 132, No. 13. pp. 1433-1438.
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