Open Access

How to regulate neutrophils in gout

Arthritis Research & Therapy201315:118

DOI: 10.1186/ar4316

Published: 25 September 2013

Abstract

Most research in gout has concentrated on the proinflammatory mechanisms toexplain the inflammation that is generated when leucocytes are in contact withmonosodium urate crystals. However, the episodic nature of gout and the absenceof inflammation even when crystals are present suggest that there are naturalcounter-regulatory mechanisms to limit the inflammatory response. Gagné andcolleagues showed that myeloid inhibitory C-type lectin, a C-type lectininhibitory receptor expressed on neutrophils, modulates monosodium urate-inducedneutrophil responses in vitro.

Neutrophil recruitment and activation play a key role in the acute inflammatoryresponse to monosodium urate (MSU) crystals. In acute gout, our current treatmentssuch as nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids all acton different steps of neutrophil activation. These drugs form part of the firsttreatment objective in gout – to relieve the painful symptoms of the acuteattack – but do not address the second objective, which is to treat theunderlying metabolic disorder hyperuricemia. Can neutrophil activation bemanipulated or regulated? Are there signals that can be modulated and can this be ofclinical relevance?

The article by Gagné and colleagues provides evidence for an inhibitory pathwayof neutrophil activation that acts through a recently described C-type lectinreceptor called the myeloid inhibitory C-type lectin (MICL) [1]. This membrane receptor, also known as CLEC12A, inhibits neutrophilactivation when it is engaged. C-type lectin receptors form a large family ofproteins that have a common type of carbohydrate-binding domain that mediate celladhesion and ligand binding in a calcium-dependent manner. Members of the C-typelectin receptors are known to participate in immune regulation, with well-knownexamples including Dectin-1 (CLE7A), DC-sign (CD209 or CLEC4L) and natural killercell receptors (Ly49 or KLRA1). The MICL protein is encoded on chromosome 12p13,closely linked to the natural killer gene complex. MICL contains a cytoplasmicimmunoreceptor tyrosine-based inhibitory motif and is expressed mainly onneutrophils and monocytes. Previous work has shown that the receptor could inhibitcellular activation [2]. The ligands that lead to MICL activation are currently unknown, as thereis only a small body of data to show that the receptor interacts with ligandsexpressed in the bone marrow, thymus and kidney [3].

In their studies, Gagné and colleagues showed that MSU crystals as well as aMICL-specific antibody downmodulated MICL expression on neutrophils. Reducing theexpression of MICL by transfecting small interfering RNA or by antibody modulationof the receptor led to enhanced production of IL-8 when MSU was added toneutrophils, but no changes in IL-1β secretion were observed. The mechanisms ofMICL signaling probably involve tyrosine phosphorylation as well as calcium flux,differing from previous results that showed MICL associated with the phosphatasesSHP-1 and SHP-2 [2]. Finally, the addition of colchicine to neutrophils abrogated thenegative effect of MSU on MICL expression.

These results showed that reduced MICL expression is associated with augmentedinflammatory responses from neutrophils, and a higher level of neutrophil MICLexpression is associated with a reduced IL-8 production in vitro. As IL-8is a major neutrophil chemoattractant, this can have important effects on neutrophilrecruitment to an inflammatory site in gout. By extrapolation, if MICL expression orsignaling could be enhanced or maintained during inflammation, the inhibitory signalmay be reinforced and thereby downregulate inflammation. The effect of colchicine inthis system is to elevate the expression of MICL, thereby increasing the inhibitorysignaling mechanisms that counteract the inflammatory process.

A number of caveats need to be mentioned in the interpretation of these results. Thedata presented were based on in vitro models of inflammation using MSU, andwe need to see how this works in vivo before coming to any conclusions, aswe have had examples where the in vivo results did not recapitulate thein vitro findings. They convincingly showed that reducing MICLexpression on the surface of neutrophils enhanced the proinflammatory signature, butthey did not show the converse – that enhanced MICL signaling can furtherdownmodulate inflammation. Furthermore, the ligands that bind and activate MICL areunknown, so we have no idea what is the signal or how to reinforce or manipulatethis signaling system. The results presented show that MSU had dual effects onneutrophils – the first is to downregulate MICL expression, and the second isto activate IL-8 production. How are these two mechanisms linked? If MSU acts mainlyon the cell membrane internalization of MICL, what is the trigger for the IL-8secretion? Notwithstanding these uncertainties, the finding that MICL modulatesneutrophil activation in gout suggests that there are a number of counter-regulatorymechanisms in operation during an inflammatory process. Identifying these mechanismsmay help us to understand the nature of gout as well as open up new therapeuticperspectives.

Abbreviations

IL: 

Interleukin

MICL: 

Myeloid inhibitory C-type lectin

MSU: 

Monosodium urate.

Declarations

Authors’ Affiliations

(1)
Service de rhumatologie, Médecine physique et réhabilitation, Hôpital orthopédique

References

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Copyright

© BioMed Central Ltd. 2013

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