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The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions.

Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, Rahfeld JU, Wolf R, Wermann M, Stephan A, Haegele M, Sedlmeier R, Graubner S, Jagla W, Müller A, Eichentopf R, Heiser U, Seifert F, Quax PH, de Vries MR, Hesse I, Trautwein D, Wollert U, Berg S, Freyse EJ, Schilling S, Demuth HU - EMBO Mol Med (2011)

Bottom Line: Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration.Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers.The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Probiodrug AG, Halle, Germany.

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IsoQC depletion results in impaired monocyte recruitment after thioglycollate challengeRepresentative FACS analysis showing the infiltrating monocyte population in QC+/+ and QC−/− mice dissected by specific staining.Quantification of infiltrating monocytes and granulocytes in QC+/+ mice (black bars) and QC−/− mice (open bars; n = 8–13, mean ± SEM).Lavage fluid from (B) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; n.s., not significant, Student's t-test, mean ± SD).Representative FACS analysis showing the infiltrating monocyte population in isoQC+/+ and isoQC−/− mice.Quantification of infiltrating monocytes and granulocytes in isoQC+/+ mice (black bars) and isoQC−/− mice (open bars; ***p < 0.001 vs. isoQC+/+ Thio, Student's t-test, n = 10–14, mean ± SEM).Lavage fluid from (E) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; ***p < 0.001 vs. pE1-CCL2 from isoQC+/+ mice, Student's t-test, mean ± SD).
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fig03: IsoQC depletion results in impaired monocyte recruitment after thioglycollate challengeRepresentative FACS analysis showing the infiltrating monocyte population in QC+/+ and QC−/− mice dissected by specific staining.Quantification of infiltrating monocytes and granulocytes in QC+/+ mice (black bars) and QC−/− mice (open bars; n = 8–13, mean ± SEM).Lavage fluid from (B) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; n.s., not significant, Student's t-test, mean ± SD).Representative FACS analysis showing the infiltrating monocyte population in isoQC+/+ and isoQC−/− mice.Quantification of infiltrating monocytes and granulocytes in isoQC+/+ mice (black bars) and isoQC−/− mice (open bars; ***p < 0.001 vs. isoQC+/+ Thio, Student's t-test, n = 10–14, mean ± SEM).Lavage fluid from (E) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; ***p < 0.001 vs. pE1-CCL2 from isoQC+/+ mice, Student's t-test, mean ± SD).

Mentions: Therefore, the results were further substantiated in a model of thioglycollate-induced peritonitis, where the CCL2 levels as well as the cell migration could be readily analyzed. The infiltrating monocyte population was determined by fluorescence-activated cell sorting (FACS) analysis using the markers 7/4 (Ly6B.2) and Ly6G. The infiltrating monocyte population shows a high expression of 7/4 (7/4high) and a low expression of Ly6G (Ly6Glow) compared to the infiltrating granulocyte population represented by high expression of 7/4 (7/4high) and Ly6G (Ly6Ghigh; Fig 3A and D). The deficiency in QC did not influence the number of monocytes and granulocytes in the peritoneal lavage fluid after thioglycollate challenge (Fig 3A and B). Accordingly, a difference in total-CCL2 and CCL2(pE1-76) levels could not be detected between QC−/− and QC+/+ mice (Fig 3C). Again, a knockout of isoQC prevented monocyte recruitment (Fig 3D and E), whereas, recruitment of granulocytes remained unaffected (Fig 3E). The specific differences in monocyte recruitment were accompanied by significantly reduced CCL2(pE1-76) concentrations in isoQC−/− mice compared to WT littermates (Fig 3F). Hence, isoQC is apparently the major enzyme for the generation of pE1-CCL2 in vivo.


The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions.

Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, Rahfeld JU, Wolf R, Wermann M, Stephan A, Haegele M, Sedlmeier R, Graubner S, Jagla W, Müller A, Eichentopf R, Heiser U, Seifert F, Quax PH, de Vries MR, Hesse I, Trautwein D, Wollert U, Berg S, Freyse EJ, Schilling S, Demuth HU - EMBO Mol Med (2011)

IsoQC depletion results in impaired monocyte recruitment after thioglycollate challengeRepresentative FACS analysis showing the infiltrating monocyte population in QC+/+ and QC−/− mice dissected by specific staining.Quantification of infiltrating monocytes and granulocytes in QC+/+ mice (black bars) and QC−/− mice (open bars; n = 8–13, mean ± SEM).Lavage fluid from (B) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; n.s., not significant, Student's t-test, mean ± SD).Representative FACS analysis showing the infiltrating monocyte population in isoQC+/+ and isoQC−/− mice.Quantification of infiltrating monocytes and granulocytes in isoQC+/+ mice (black bars) and isoQC−/− mice (open bars; ***p < 0.001 vs. isoQC+/+ Thio, Student's t-test, n = 10–14, mean ± SEM).Lavage fluid from (E) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; ***p < 0.001 vs. pE1-CCL2 from isoQC+/+ mice, Student's t-test, mean ± SD).
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fig03: IsoQC depletion results in impaired monocyte recruitment after thioglycollate challengeRepresentative FACS analysis showing the infiltrating monocyte population in QC+/+ and QC−/− mice dissected by specific staining.Quantification of infiltrating monocytes and granulocytes in QC+/+ mice (black bars) and QC−/− mice (open bars; n = 8–13, mean ± SEM).Lavage fluid from (B) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; n.s., not significant, Student's t-test, mean ± SD).Representative FACS analysis showing the infiltrating monocyte population in isoQC+/+ and isoQC−/− mice.Quantification of infiltrating monocytes and granulocytes in isoQC+/+ mice (black bars) and isoQC−/− mice (open bars; ***p < 0.001 vs. isoQC+/+ Thio, Student's t-test, n = 10–14, mean ± SEM).Lavage fluid from (E) was analyzed for total-CCL2 (black bars) and pE1-CCL2 (open bars; ***p < 0.001 vs. pE1-CCL2 from isoQC+/+ mice, Student's t-test, mean ± SD).
Mentions: Therefore, the results were further substantiated in a model of thioglycollate-induced peritonitis, where the CCL2 levels as well as the cell migration could be readily analyzed. The infiltrating monocyte population was determined by fluorescence-activated cell sorting (FACS) analysis using the markers 7/4 (Ly6B.2) and Ly6G. The infiltrating monocyte population shows a high expression of 7/4 (7/4high) and a low expression of Ly6G (Ly6Glow) compared to the infiltrating granulocyte population represented by high expression of 7/4 (7/4high) and Ly6G (Ly6Ghigh; Fig 3A and D). The deficiency in QC did not influence the number of monocytes and granulocytes in the peritoneal lavage fluid after thioglycollate challenge (Fig 3A and B). Accordingly, a difference in total-CCL2 and CCL2(pE1-76) levels could not be detected between QC−/− and QC+/+ mice (Fig 3C). Again, a knockout of isoQC prevented monocyte recruitment (Fig 3D and E), whereas, recruitment of granulocytes remained unaffected (Fig 3E). The specific differences in monocyte recruitment were accompanied by significantly reduced CCL2(pE1-76) concentrations in isoQC−/− mice compared to WT littermates (Fig 3F). Hence, isoQC is apparently the major enzyme for the generation of pE1-CCL2 in vivo.

Bottom Line: Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration.Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers.The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Probiodrug AG, Halle, Germany.

Show MeSH
Related in: MedlinePlus