A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization.

Matrix metalloproteinase-8 (MMP8) has been shown to influence various cellular functions. As monocytes and macrophages (Mφ) express MMP8, we investigated if MMP8 played a role in macrophage differentiation and polarization. MMP8 expression was significantly increased during monocyte differentiation into Mφ. Monocyte-derived Mφ from MMP8-deficient mice expressed higher levels of M1-Mφ markers but lower levels of M2-Mφ markers than monocyte-derived Mφ from wild-type mice. Although Mφ from either MMP8-deficient or wild-type mice were inducible by interferon-γ into M1-Mφ, only wild-type Mφ but not MMP8-deficient Mφ could be induced into M2-Mφ by interleukin-4. However, MMP8-deficient Mφ exposed to conditioned culture media of wild-type Mφ developed a M2-Mφ phenotype. Compared with conditioned culture media of wild-type Mφ, conditioned culture media of MMP8-deficient Mφ contained a lower concentration of active transforming growth factor-β (TGF-β), an M2-Mφ inducer. Moreover, evidence also showed that the degradation of the TGF-β sequester, fibromodulin, was modulated by MMP8. The data indicate a previously unknown role of MMP8 in M2-Mφ polarization by cleaving fibromodulin and therefore increasing the bioavailability of the M2-Mφ inducer TGF-β

Plasma SDF1α levels and circulating EPC numbers according to <i>SDF1</i> and <i>CXCR4</i> SNP genotypes.

<p>SDF-1 levels and EPC numbers (per 1 ml blood) are age- and sex-adjusted arithmetic (95%CI) and geometric means (95%CI), respectively. P values are from general linear models adjusted for age and sex and in brackets from models additionally adjusted for canditate vascular risk factors and determinants of SDF-1α levels (LDL and HDL cholesterol [mg/dL], smoking [0,1], hypertension [0,1], diabetes [0,1], alcohol consumption [gram/day], homocystein [µmol/L], hsCRP [mg/L], MMP9 [ng/mL], cystatin C [mg/L], fibrinogen [mg/dL]).</p

Figure 1

<p>Panel A shows near normal distribution of SDF1α in the Bruncek study population. Panel B displays the association between SDF-1α measured in 2000 and in 2005 and age (r = 0.270, p<0.001). Panel C illustrates the correlation between SDF1α levels and EPC number in 2005. The regression line demonstrates clearly that SDF1α levels are inverse association with EPC number. Panel D illustrates the association between EPC numbers in 2005 and SDF1α level in 2000 (tertile groups). SDF-1 tertile groups are defined as follows: T1<2409, T2 2409–2753 and T3>2753. The box plots indicating EPC number median and IQRs. Notably, EPC numbers are significant associated inversely with SDF-1α levels, especially much low EPC number were likely observed in the top tertile group of SDF-1 levels.</p

Genotype and allele frequencies of <i>SDF1</i> and <i>CXCR4</i> SNPs studied

<p>Genotype and allele frequencies of <i>SDF1</i> and <i>CXCR4</i> SNPs studied</p

Associations of the SDF1 rs2297630 SNP (2000) with EPC number (median and IQR, A) and blood SDF1α level (arithmetic means and SD, B) assessed in the 2005 evaluation of the Bruneck Study.

<p>Associations of the SDF1 rs2297630 SNP (2000) with EPC number (median and IQR, A) and blood SDF1α level (arithmetic means and SD, B) assessed in the 2005 evaluation of the Bruneck Study.</p

Association between SDF-1α level and selected vascular risk factors and laboratory parameters (2005).

<p>Values are means ±SD. P values for trend are from age- and sex-adjusted analyses.</p

Population characteristics according to PTX3 tertile groups in the Bruneck Study.

a<p>Values presented are means±SD, medians (IQR) or numbers (%).</p>b<p>P values are for trend and derived from age- and sex-adjusted linear or logistic regression analysis of each variable on log_e-transformed PTX3 level. When correcting for multiple testing, a P value<0.002 <b>(in bold)</b> indicates statistical significance (Bonferroni adjustment).</p><p>Urinary ACR – Urinary albumin-to-creatinine ratio; hsCRP – high-sensitivity C-reactive Protein; MMP-9 – matrix metalloproteinase-9; G-CSF – granulocyte colony stimulating factor; SDF-1 – stromal cell-derived factor-1; VEGF – vascular endothelial growth factor.</p

Measures of carotid and femoral artery atherosclerosis according to CRP tertile groups in the Bruneck Study.

<p>Values presented are means±SD. Analyses were conducted in the entire population (All) and separately in those free of CVD (No CVD). P values are for trend and derived from age/sex-adjusted and multivariable (adjustment see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031474#pone-0031474-t003" target="_blank">Table 3</a>) linear regression analysis of each variable on log_e-transformed PTX3 level. P values in brackets are those from the multivariable models. AS, atherosclerosis score.</p

Measures of carotid and femoral artery atherosclerosis according to PTX3 tertile groups in the Bruneck Study.

<p>Values presented are means±SD. Analyses were conducted in the entire population (All) and separately in those free of CVD (No CVD). P values are for trend and derived from age/sex-adjusted and multivariable (adjustment for age, sex, diabetes, hypertension, HDL and LDL cholesterol, smoking body mass index and waist circumference) linear regression analysis of each variable on log_e-transformed PTX3 level. P values in brackets are those from the multivariable models. AS, atherosclerosis score.</p

Contribution of PTX3 and C-reactive protein level or the combination of the two to the risk prediction of prevalent cardiovascular disease.

<p>*The multivariable logistic regression model was adjusted c. The composite cardiovascular endpoint subsumes all cases of ischemic stroke, TIA, myocardial infarction, peripheral artery disease, definite angina and previous revascularization procedures (n = 95).</p>†<p>Variable chi-square is the 1-degree-of-freedom likelihood ratio chi-square statistic with P values for inclusion of each variable separately to the multivariable base model, with larger values indicating greater improvement in fit. The+sign indicates the addition of either PTX3 level, or C-reactive protein level, or both to the base model considering standard risk factors.</p>‡<p>The calibration P values was calculated with the Hosmer-Lemeshow calibration statistics comparing observed and predicted risk in decile categories of predicted risk. Higher values for the calibration P value reflect better fit.</p>§<p>The C statistic represents the area under the receiver-operating-characteristic curve. Higher values for the C statistic reflect better fit.</p>#<p>non normally distributed PTX3 and hsCRP levels were log-transformed.</p