M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway

Madsen, Daniel H.; Leonard, D.M.; Masedunskas, Andrius; Moyer, Amanda; Jürgensen, Henrik J.; Peters, Diane E.; Amornphimoltham, Panomwat; Selvaraj, Arul; Yamada, Susan S.; Brenner, David A.; Burgdorf, Sven; Engelholm, Lars H.; Behrendt, Niels; Holmbeck, Kenn; Weigert, Roberto; Bugge, Thomas H.

doi:10.1083/jcb.201301081

Cited by 299 publications

(270 citation statements)

References 66 publications

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“…Activated macrophages, including M2-polarized macrophages, have been implicated in supporting angiogenesis and inflammation as multiple factors secreted by these cells exhibit pro-angiogenic activities (35,62). Although many studies indicate that synthetic RGD-containing peptides inhibit angiogenesis and tumor growth, our findings provide the first evidence that macrophages may generate and release an RGDKGE-containing collagen epitope that may exhibit pro-angiogenic activity.…”

Section: Discussionmentioning

confidence: 59%

“…Interestingly, mAb XL313-and XL166-reactive RGD epitopes did not exhibit a typical extracellular fibril collagen pattern, but rather they exhibited punctate distribution with both intracellular and scattered extracellular localization. The intracellular distribution is similar to the staining pattern of collagen degradation products previously documented within intracellular vesicles of macrophages (35). Given the generation of these distinct sets of RGD-containing epitopes, we next examined whether they may play active roles in regulating angiogenesis and inflammation.…”

Section: Resultsmentioning

confidence: 79%

“…Analysis of angiogenic CAM tissues suggests that a subset of macrophages may be an important source of the RGDKGE epitope. Activated macrophages with M2-like characteristics can express multiple enzymes capable of degrading collagen and in turn can internalize and further degrade collagen into small low molecular weight fragments (35,38). Although little evidence exists that macrophages generate and deposit intact triple helical collagen type I, studies have indicated that certain isoforms of collagen may be expressed (61).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of cells, including fibroblasts and endothelial cells, can express collagen, and moreover, partially degraded collagen can be internalized and further processed by activated M2-like macrophages leading to the generation of low molecular weight fragments (35,38). Given the unique pattern of mAb XL313 immunoreactivity observed in vivo, we examined whether stromal cells associated with angiogenesis and inflammation could generate the RGDKGE-containing epitope.…”

Section: Peptidementioning

confidence: 99%

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Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin ␣v␤3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by ␣v␤3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting ␣v␤3 signaling, this collagen epitope promoted ␣v␤3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates ␣v␤3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control ␣v␤3 signaling by targeting a proangiogenic and inflammatory ligand of ␣v␤3 rather than the receptor itself.

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Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Peptidementioning

confidence: 99%

See 2 more Smart Citations

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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“…28 As shown in Figure 8B, CL treatment increased the CD206 + cell fraction, which is known to participate in matrix collagen endocytosis (Supplemental Figure 9). 29 Patent fibrosis could be observed in the glycerol-treated mice, as assessed by collagen III deposits and Masson trichrome staining ( Figure 8C). Consistent with the effect observed at day 2, CL led to a reduction of collagen III deposits (Figure 8, C and D).…”

Section: Rhabdomyolysis Drastically Affects the Kidney Macrophage Phementioning

confidence: 99%

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Béllière¹,

Casemayou²,

Ducassé³

et al. 2015

Journal of the American Society of Nephrology

130

123

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Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysisinduced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. rophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysisinduced AKI progression and advocate the utility of long-term follow-up for patients with this disease.

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High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

et al. 2020

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Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma‐promoting, alternatively activated M2‐like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor‐associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)‐conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B‐cell lymphoma (DLBCL) cells or, classically, by macrophage colony‐stimulating factor (M‐CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD‐L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M‐CSF stimulation in M2‐like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose‐dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL‐TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co‐cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma‐only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206‐positive cells, with high MRC1 expression being characteristic of HL‐stage IV. In summary, the lymphoma‐TAM interaction contributes to matrix‐remodeling and lymphoma cell dissemination.

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M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway

Abstract: Mannose receptor–mediated uptake of collagen by M2-like macrophages is a major mechanism of collagen turnover in mice.

Cited by 299 publications

References 66 publications

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

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