CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray.

Corinna Lau,Ole-Lars Brekke,Hilde Fure,Ole Kristoffer Olstad,Marit Holden,Ståle Nygård,Knut Tore Lappegård,Terje Espevik,Eivind Hovig,Tom Eirik Mollnes

doi:10.1371/journal.pone.0117261

Abstract

Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.

Highlights

Systemic inflammatory conditions are major health problems
Systemic inflammation can be induced by a broad variety of exogenous and endogenous danger signals represented by pathogen-associated molecular patterns (PAMPs), such as bacterial toxins and structural components, fungi, and viral nucleic acids, as well as damage-associated molecular patterns (DAMPs), such as necrotic cells and endocrine glycolipids [5]
We report that combined inhibition of CD14 and C3 most efficiently reduced the transcriptional response to E. coli–contained molecular patterns in a human whole blood model, which aims to mimic systemic inflammation

Summary

Introduction

Systemic inflammatory conditions are major health problems. For sepsis, which has a lethality rate of 20% to 60%, we lack both effective therapeutics and specific diagnostic markers. We hypothesize that upstream targeting of the innate immune response by combined inhibition of complement and Toll-like receptor (TLR) signaling at the levels of complement factors C3 or C5 and TLR co-receptor CD14, respectively, may constitute a suitable therapeutic strategy for broad and early treatment of acute systemic inflammation [3,4]. PAMPs and DAMPs are recognized by pattern recognition receptors (PRRs) of the host innate immune system, including TLRs and the complement system. CD14 is a key molecule in TLR signaling and C3 and C5 are key molecules of the complement system. Together, they represent potential candidates for therapeutic targeting [3]

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Conclusion