Abstract
BackgroundLow C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet’s disease (BD). The objective of the present study was to clarify the pathological roles of CCR1 and IL10 loci identified by previous BD genome-wide association studies (GWASs).MethodsM1 and M2 macrophages (Mφ) were differentiated with granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor (M-CSF) from peripheral monocytes of healthy control subjects (HC) and patients with BD. Expression of CD68 and CD163 was evaluated to test for Mφ polarization. CCR1 and IL-10 messenger RNA (mRNA) and protein expression was compared according to CCR1 and IL10 single-nucleotide polymorphism (SNP) genotypes. The migratory ability of M1 and M2 Mφ toward CCR1 ligand macrophage inflammatory protein (MIP)-1α was compared. The ratio of M1 and M2 Mφ in skin lesions of BD and systemic sclerosis (SSc), which was reported to be M2 Mφ-dominant, was compared. To examine the plasticity of polarized Mφ, the differentiated cells were cultured with either the same or the other culture condition.ResultsPreferential expression of CD163, CCR1, and IL-10 was found in M2 Mφ compared with M1 Mφ. M2 Mφ migrated more sensitively to low concentrations of MIP-1α than M1 Mφ did. BD-derived M1 Mφ showed higher CCR1 surface expression than HC-derived M1 Mφ did. IL10 and CCR1 mRNA expression differences were observed by GWAS-identified SNP genotypes in polarized Mφ. BD skin lesions showed M1 Mφ predominance compared with SSc skin lesions. A plasticity assay revealed that M-CSF restored IL-10 synthesis and reduced IL-6 production by M1 Mφ.ConclusionsThe present study reveals that GWAS-identified SNPs contribute to M1 Mφ-predominant inflammation in BD. Our data also suggest that the skewed Mφ polarization is correctable by immunological intervention.
Highlights
Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet’s disease (BD)
We previously reported that the disease risk allele of IL10 locus rs1518111 is associated with reduced production of IL-10, as well as of CCR1 locus rs7616215, an single-nucleotide polymorphism (SNP) in the 3′ noncoding region, and that it is associated with lower CCR1 messenger RNA expression and reduced monocyte chemotaxis [5]
The results showed that CCR1 surface expression of M1 Mφ was significantly increased in BD compared with healthy control subjects (HC) (Fig. 2a), whereas no difference was detected in M2 Mφ (Fig. 2b)
Summary
Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet’s disease (BD). Behçet’s disease (BD) is an idiopathic inflammatory disease that affects multiple organs, including the skin, eyes, vasculum, and mucosa [1, 2] Genetic factors such as HLA-B*51, as well as environmental factors, including microbial components, have been implicated in the pathogenesis of BD [3]. The result was unexpected because the low chemotactic ability of monocytes, which seems to be protective from inflammation, was identified as a risk for BD This genetic findings do not directly correspond to previous functional studies that have shown excessive production of Mφ-derived proinflammatory cytokines, including tumor necrosis factor (TNF)-α, which is the most effective therapeutic target in BD [16, 17]. Our recent genetic study suggested that an effective target may be the IL1A–IL1B locus, which is related to enhanced IL-1β production from activated Mφ [10]
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