Objectives: To study the phenotype of macrophage infiltrates and their role in angiogenesis in different Idiopathic Inflammatory Myopathies (IIMs). Methods: The density and distribution of the subpopulations of macrophages subsets (M1, inducible nitric oxide+, CD11c+; M2, arginase-1+), endomysial capillaries (CD31+, FLK1+), degenerating (C5b-9+), and regenerating (NCAM+) myofibers, were investigated by immunohistochemistry in human muscle samples of diagnostic biopsies from a large cohort of untreated patients (n: 81) suffering from anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR)+ Immune Mediated Necrotizing Myopathy (IMNM), anti-signal recognition particle (anti-SRP)+ IMNM, seronegative IMNM, Dermatomyositis, Polymyositis, Polymyositis with mitochondrial pathology, sporadic Inclusion Body Myositis, Scleromyositis, and anti-Synthetase Syndrome. The samples were compared with mitochondrial myopathy and control muscle samples. Results: Compared with the other IIMs and controls, endomysial capillary density (CD) was higher in anti-HMGCR+ IMNM, where M1 and M2 macrophages, detected by confocal microscopy, infiltrated perivascular endomysium and expressed angiogenic molecules such as VEGF-A and CXCL12. These angiogenic macrophages were preferentially associated with CD31+ FLK1+ microvessels in anti-HMGCR+ IMNM. The VEGF-A+ M2 macrophage density was significantly correlated with CD (rS: 0.98; p: 0.0004). Western blot analyses revealed increased expression levels of VEGF-A, FLK1, HIF-1α, and CXCL12 in anti-HMGCR+ IMNM. CD and expression levels of these angiogenic molecules were not increased in anti-SRP+ and seronegative IMNM, offering additional, useful information for differential diagnosis among these IIM subtypes. Conclusion: Our findings suggest that in IIMs, infiltrating macrophages and microvascular cells interactions play a pivotal role in coordinating myogenesis and angiogenesis. This reciprocal crosstalk seems to distinguish anti-HMGCR associated IMNM.

Perivascular and endomysial macrophages expressing VEGF and CXCL12 promote angiogenesis in anti-HMGCR immune-mediated necrotizing myopathy

Lia, Anna
Membro del Collaboration Group
;
Annese, Tiziana
Membro del Collaboration Group
;
Fornaro, Marco
Membro del Collaboration Group
;
Giannini, Margherita
Membro del Collaboration Group
;
D'Abbicco, Dario
Membro del Collaboration Group
;
Errede, Mariella
Membro del Collaboration Group
;
Lorusso, Loredana
Membro del Collaboration Group
;
Trojano, Maria
Supervision
;
Virgintino, Daniela
Supervision
;
Ribatti, Domenico
Supervision
;
Iannone, Florenzo
Supervision
;
Girolamo, Francesco
Membro del Collaboration Group
2021

Abstract

Objectives: To study the phenotype of macrophage infiltrates and their role in angiogenesis in different Idiopathic Inflammatory Myopathies (IIMs). Methods: The density and distribution of the subpopulations of macrophages subsets (M1, inducible nitric oxide+, CD11c+; M2, arginase-1+), endomysial capillaries (CD31+, FLK1+), degenerating (C5b-9+), and regenerating (NCAM+) myofibers, were investigated by immunohistochemistry in human muscle samples of diagnostic biopsies from a large cohort of untreated patients (n: 81) suffering from anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR)+ Immune Mediated Necrotizing Myopathy (IMNM), anti-signal recognition particle (anti-SRP)+ IMNM, seronegative IMNM, Dermatomyositis, Polymyositis, Polymyositis with mitochondrial pathology, sporadic Inclusion Body Myositis, Scleromyositis, and anti-Synthetase Syndrome. The samples were compared with mitochondrial myopathy and control muscle samples. Results: Compared with the other IIMs and controls, endomysial capillary density (CD) was higher in anti-HMGCR+ IMNM, where M1 and M2 macrophages, detected by confocal microscopy, infiltrated perivascular endomysium and expressed angiogenic molecules such as VEGF-A and CXCL12. These angiogenic macrophages were preferentially associated with CD31+ FLK1+ microvessels in anti-HMGCR+ IMNM. The VEGF-A+ M2 macrophage density was significantly correlated with CD (rS: 0.98; p: 0.0004). Western blot analyses revealed increased expression levels of VEGF-A, FLK1, HIF-1α, and CXCL12 in anti-HMGCR+ IMNM. CD and expression levels of these angiogenic molecules were not increased in anti-SRP+ and seronegative IMNM, offering additional, useful information for differential diagnosis among these IIM subtypes. Conclusion: Our findings suggest that in IIMs, infiltrating macrophages and microvascular cells interactions play a pivotal role in coordinating myogenesis and angiogenesis. This reciprocal crosstalk seems to distinguish anti-HMGCR associated IMNM.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/381789
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