Infiltration of M2‐polarized macrophages in infected lymphatic malformations: possible role in disease progression

Zhang, W.; He, Kefei; Yang, Jiegang; Ren, Jian‐Gang; Sun, Yanfang; Zhao, Jianhua; Zhao, Yi‐Fang

doi:10.1111/bjd.14471

Cited by 14 publications

(16 citation statements)

References 32 publications

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“…9 Our previous study has demonstrated that LMs with infection showed enhanced lymphangiogenesis. 10 Moreover, consistent with the study from other investigators, 11 our research 10 has revealed that tertiary lymphoid organs (TLOs), which were composed of aggregated lymphocytes in a highly organized manner and resembled normal secondary lymphoid organs (eg, lymph nodes), were commonly seen in human LMs. In addition, the TLOs contribute to new lymphatic vessel formation.…”

supporting

confidence: 84%

Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation

Yang

Sun²,

et al. 2017

The American Journal of Pathology

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Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin β receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.

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supporting

confidence: 84%

Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation

Yang

Sun²,

et al. 2017

The American Journal of Pathology

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“…We analysed and compared the number of CD68 + /H‐ferritin + cells with the number of CD68‐/H‐ferritin + cells, pointing out that a large percentage of H‐ferritin + cells expressed CD68 (CD68 + /H‐ferritin + cells: 5 median, range = 2·7; 9·0 versus CD68‐/H‐ferritin + cells 1·7 median, range = 1·5; 2·2; P < 0·0001). In addition, we analysed possible co‐localizations among the H‐ferritin and IL‐12, which is considered an M1 macrophage marker, and CD163, which is considered an M2 macrophage marker, as shown previously . As shown in Fig.…”

Section: Resultsmentioning

confidence: 93%

“…This is a member of the TIM gene family and is expressed by T helper type 2 (Th2) cells and macrophages in the context of the proinflammatory milieu [32,33]. The binding H-ferritin/TIM-2 may activate these immune cells, leading to subsequent pathogenic proinflammatory process [12,[18][19][20][21]. Taking together all these mechanisms, it is possible to speculate that the enhanced tissue expression of H-ferritin, via a vicious loop, may perpetuate the production of proinflammatory cytokines, possible therapeutic targets in MAS [16,17,22,23,27,28].…”

Section: Discussionmentioning

confidence: 99%

H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

Ruscitti

Cipriani

Benedetto

et al. 2017

Clinical and Experimental Immunology

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Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68 /H-ferritin and CD68 /L-ferritin ; and (iii) interleukin (IL)-1β, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1β, TNF and IFN-γ were increased significantly in MAS. Furthermore, an increased number of CD68 /H-ferritin cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68 /H-ferritin cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68 /L-ferritin cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68 /H-ferritin cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68 /H-ferritin were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.

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“…Our analyses show a positive correlation between the number of CD68 1 /H-ferritin 1 in the skin of AOSD patients and the multi-visceral involvement of the disease (P < 0Á05). Subsequently, we performed a double staining between the H-ferritin and IL-12, a well-known M1 macrophage marker, and CD163, which is considered a M2 macrophage marker [24,25]. In our samples, we observed a strong infiltrate of cells co-expressing H-ferritin and IL-12, suggesting that M1 macrophages colonize the affected skin.…”

Section: Cd68 1 /H-ferritin 1 Macrophages In Aosd Skinmentioning

confidence: 81%

H-ferritin and CD68+/H-ferritin+ monocytes/macrophages are increased in the skin of adult-onset Still's disease patients and correlate with the multi-visceral involvement of the disease

Ruscitti

Cipriani

Ciccia

et al. 2016

Clinical and Experimental Immunology

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Adult-onset Still's disease (AOSD) patients may show an evanescent salmon-pink erythema appearing during febrile attacks and reducing without fever. Some patients may experience this eruption for many weeks. During AOSD, exceptionally high serum levels of ferritin may be observed; it is an iron storage protein composed of 24 subunits, heavy (H) subunits and light (L) subunits. The ferritin enriched in L subunits (L-ferritin) and the ferritin enriched in H subunits (H-ferritin) may be observed in different tissues. In this work, we aimed to investigate the skin expression of both H-and L-ferritin and the number of macrophages expressing these molecules from AOSD patients with persistent cutaneous lesions. We observed an increased expression of H-ferritin in the skin, associated with an infiltrate in the biopsies obtained from persistent cutaneous lesions of AOSD patients. Furthermore, a positive correlation between H-ferritin skin levels as well as the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed. Our data showed an increased expression of H-ferritin in the skin of AOSD patients, associated with a strong infiltrate of CD68(+) /H-ferritin(+) cells. Furthermore, a correlation between the levels of H-ferritin as well as of the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed.

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Infiltration of M2‐polarized macrophages in infected lymphatic malformations: possible role in disease progression

Abstract: M2-polarized macrophages that may be recruited through TLOs in infected LMs may contribute to the progression of the disease by secreting VEGF-C, and therefore accelerating the proliferation of lymphatic endothelial cells.

Cited by 14 publications

References 32 publications

Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation

Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation

H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

H-ferritin and CD68+/H-ferritin+ monocytes/macrophages are increased in the skin of adult-onset Still's disease patients and correlate with the multi-visceral involvement of the disease

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