Environmental conditioning in the control of macrophage thrombospondin-1 production

Fordham, Jezrom B.; Hua, Jing; Morwood, Sarah R.; Schewitz-Bowers, Lauren P; Copland, David A; Dick, Andrew D.; Nicholson, Lindsay B.

doi:10.1038/srep00512

Cited by 32 publications

(29 citation statements)

References 43 publications

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“…Consistent with our earlier report, 16 these results further reinforce the assertion that M1 or M2 phenotype alone does not entirely determine functional outcome in promoting or regulating angiogenesis because macrophages integrate complex microenvironment and cytokine cues through time. 49 Although both Th2 cytokines drove sFlt-1 responses and induced macrophage-mediated inhibition on HUVEC proliferation, the effect of IL-4 was more pronounced. IL-4 and IL-13 trigger similar biological functions and signaling cascades, 50 and to demonstrate a requirement for signaling via the IL-4R we used BMDMs from IL-4 receptor-deficient mice and demonstrated that these cells failed to up-regulate sFlt-1 gene or protein expression when stimulated with recombinant IL-4 ( Figure 4).…”

Section: Il-4 Inhibition Of Angiogenesismentioning

confidence: 98%

IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis

Georgiadis

Copland

et al. 2015

The American Journal of Pathology

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One of the main drivers for neovascularization in age-related macular degeneration is activation of innate immunity in the presence of macrophages. Here, we demonstrate that T helper cell type 2 cytokines and, in particular, IL-4 condition human and murine monocyte phenotype toward Arg-1(+), and their subsequent behavior limits angiogenesis by increasing soluble fms-like tyrosine kinase 1 (sFlt-1) gene expression. We document that T helper cell type 2 cytokine-conditioned murine macrophages neutralize vascular endothelial growth factor-mediated endothelial cell proliferation (human umbilical vein endothelial cell and choroidal vasculature) in a sFlt-1-dependent manner. We demonstrate that in vivo intravitreal administration of IL-4 attenuates laser-induced choroidal neovascularization (L-CNV) due to specific IL-4 conditioning of macrophages. IL-4 induces the expression of sFlt-1 by resident CD11b(+) retinal microglia and infiltrating myeloid cells but not from retinal pigment epithelium. IL-4-induced suppression of L-CNV is not prevented when sFlt-1 expression is attenuated in retinal pigment epithelium. IL-4-mediated suppression of L-CNV was abrogated in IL-4R-deficient mice and in bone marrow chimeras reconstituted with myeloid cells that had undergone lentiviral-mediated shRNA silencing of sFlt-1, demonstrating the critical role of this cell population. Together, these data establish how lL-4 directly drives macrophage sFlt-1 production expressing an Arg-1(+) phenotype and support the therapeutic potential of targeted IL-4 conditioning within the tissue to regulate disease conditions such as neovascular age-related macular degeneration.

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Section: Il-4 Inhibition Of Angiogenesismentioning

confidence: 98%

IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis

Georgiadis

Copland

et al. 2015

The American Journal of Pathology

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“…Serine protease HTRA1/age related maculopathy susceptibility protein 2 genes are critical for the production of transforming growth factor, which plays an important role in the control of inflammation and interacts with matricellular proteins such as thrombospondin. 25 …”

Section: An Aging Retina Vs An Aging Immune Systemmentioning

confidence: 99%

Immune Responses in Age-Related Macular Degeneration and a Possible Long-term Therapeutic Strategy for Prevention

Nussenblatt¹,

Lee²,

Chew³

et al. 2014

American Journal of Ophthalmology

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Purpose To describe the immune alterations associated with, age related macular degeneration (AMD). Based on these findings, to offer an approach to possibly prevent the expression of late disease. Design Perspective Methods Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients. Results Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin-17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occurs throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed immunotherapy has been shown to affect the late stages of AMD. Conclusion Immune dysregulation appears to be an underlying alteration in AMD as in other diseases thought to be degenerative and due to aging. Parainflammation and immunosensescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin-17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression.

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“…TSP-1 is a major component of platelets alpha granules: pre-synthetised protein is released upon platelets activation (126, 127). Macrophages also regulate TSP-1 secretion: the secretion is induced by LPS, and the threshold for the level of secretion is regulated by the environmental signals, including the mediators of the adaptive immune system, Th1 and Th2 cytokines (128). TSP-1 secretion depends on cell density in culture: lower density results in higher secretion of TSP-1 by fibroblasts, endothelial and smooth muscle cells without change in protein synthesis (129).…”

Section: Introductionmentioning

confidence: 99%

Invoking the power of thrombospondins: Regulation of thrombospondins expression

Stenina‐Adognravi¹

2014

Matrix Biology

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Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and pathological processes. With the growing understanding of the importance of these matricellular proteins, the need to understand the mechanisms of regulation of their expression and potential approaches to modulate their levels is also increasing. The regulation of TSPs expression is multi-leveled, cell- and tissue-specific, and very precise. However, the knowledge of mechanisms modulating the levels of TSPs is fragmented and incomplete. This review discusses the known mechanisms of regulation of TSPs levels and the gaps in our knowledge that prevent us from developing strategies to modulate the expression of these physiologically important proteins.

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Environmental conditioning in the control of macrophage thrombospondin-1 production

Cited by 32 publications

References 43 publications

IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis

IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis

Immune Responses in Age-Related Macular Degeneration and a Possible Long-term Therapeutic Strategy for Prevention

Invoking the power of thrombospondins: Regulation of thrombospondins expression

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