Polymorphonuclear Neutrophils in Rheumatoid Arthritis and Systemic Lupus Erythematosus: More Complicated Than Anticipated

Ahmad Haidar Ahmad,Patrice Decker,Dyhia Melbouci

doi:10.3390/immuno2010007

Abstract

Polymorphonuclear neutrophils (PMN) are the most abundant leucocytes in the circulation in humans. They represent a heterogeneous population exerting diverse functions through several activities. Usually described as typical pro-inflammatory cells, immunomodulatory properties of PMNs have been reported. Among others, once activated and depending on the stimulus, PMNs expel neutrophil extracellular traps (NET) in the extracellular space. NETs are complexes made of DNA and granule proteins representing an innate immune mechanism fighting infections. Nevertheless, an excess of NET formation might be involved in the development of inflammatory or autoimmune responses. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two chronic, inflammatory, autoimmune diseases of unknown etiology and affecting mostly women. Several abnormal or non-classical functions of PMNs or PMN sub-populations have been described in SLE and RA. Particularly, NETs have been suggested to trigger pro-inflammatory responses by exposing pro-inflammatory mediators. Likewise, NETs may be the targets of autoantibodies or even might trigger the development of autoantibodies by exposing autoantigens. In the present review, we will summarize heterogeneous properties of human PMNs and we will discuss recent evidence linking PMNs and NETs to the pathogenesis of both SLE and RA.

Highlights

Many data support a key role for Polymorphonuclear neutrophils (PMN) in rheumatoid arthritis (RA) and Systemic lupus erythematosus (SLE) pathogenesis
Many of them suggest that PMNs are involved through the formation of neutrophil extracellular traps (NET) while others highlight PMN
Several pathogenic mechanisms are potentially common to RA and SLE, but they are probably finely regulated in response to stimuli which are more disease specific

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Activated PMNs have been shown to produce and release neutrophil extracellular traps (NET), complexes of DNA and proteins from granules [3]. In response to phorbol myristate acetate (PMA, a protein kinase C agonist), IL-8 or LPS, PMNs were originally shown to release in the extracellular environment structures composed of nuclear DNA filaments decorated with histones (namely chromatin filaments) and associated with granule proteins, but devoid of membrane These fibers are capable of trapping and killing gram-positive and gram-negative bacteria, highlighting a new innate immune mechanism to neutralize and remove pathogenic bacteria by neutrophils. Different mechanisms and pathways of NET formation have been described [63,64], leading to PMN death or not, depending on the stimulus In the latter case, this process is named vital (or live) NETosis. NETs are engulfed by macrophages, a process facilitated when NETs are opsonized by C1q [77] or LL-37 [76], and are degraded intracellularly

Involvement of PMNs in RA and SLE

Involvement in SLE Pathogenesis

Involvement in RA Pathogenesis

Findings

Conclusions