Amniotic Membrane Induces Peroxisome Proliferator-Activated Receptor-γ Positive Alternatively Activated Macrophages

Bauer, Dirk; Hennig, Maren; Wasmuth, Susanne; Baehler, Hanna; Busch, Martin; Steuhl, Klaus‐Peter; Thanos, Solon; Heiligenhaus, Arnd

doi:10.1167/iovs.11-7617

Cited by 30 publications

(26 citation statements)

References 70 publications

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“…5), a M2a marker typically generated by IL-4/IL-13 (87). The latter finding is consistent with a previous report showing PPAR-␥ is up-regulated in corneal macrophages after AM transplanted to corneas infected with herpes simplex virus (39). We suspect that such broad spectrum of M2 polarization by immobilized HC-HA may be linked to the suppression of the nuclear translocation of IRF5 because IRF5 is known to transcriptionally activate IL-12p40 (60), TNF-␣ (88, 89), and NOS2 (90) but down-regulate IL-10 (60).…”

Section: Discussionsupporting

confidence: 92%

“…2). Collectively, these data corroborate the previous studies based on AM (33,34,40) and AME (41) while beginning to explain the mechanism of their anti-inflammatory effects via promotion of apoptosis of activated neutrophils (33,34,37), macrophages (35,37,39), and probably lymphocytes (36).…”

Section: Discussionsupporting

confidence: 88%

“…30 -32). Application of cryopreserved human AM reduces infiltration of neutrophils in the excimer-ablated rabbit corneal stroma while promoting apoptosis of neutrophils (33,34); traps and causes apoptosis of monocytes and macrophages during the treatment of human corneal epithelial defects (35); induces rapid regression of corneal stromal edema and inflammation by reducing infiltration of lymphocytes (36), neutrophils (37), and macrophages (37,38); and promotes M2a phenotype in the corneal stroma of murine HSV-1 necrotizing keratitis (39). These in vivo data are supported by in vitro findings that human AM induces apoptosis of IFN-␥ activated monocyte/macrophage RAW264.7 cells (40).…”

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confidence: 99%

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Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

He¹,

Zhang²,

Tighe³

et al. 2013

Journal of Biological Chemistry

115

118

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Background: HC-HA is a unique anti-inflammatory matrix different from hyaluronic acid (HA). Results: Soluble HC-HA induces apoptosis of inflammatory neutrophils and macrophages, and immobilized HC-HA promotes M2 polarization upon LPS/TLR ligation while both enhancing macrophage phagocytosis. Conclusion: HC-HA exerts its anti-inflammatory action using multiple mechanisms. Significance: HC-HA is the first known matrix component to polarize M2b.Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-␣-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPSactivated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-␣, and NO synthase 2. Additionally, IL-10, TGF-␤1, peroxisome proliferator-activated receptor ␥, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes.Inflammation serves as the first host response to real or perceived threats to tissue homeostasis. It is heralded by the recruitment of neutrophils, which eliminate pathogens and damaged tissues before eventually undergoing apoptosis (1-3). These apoptotic neutrophils are then removed by macrophages via phagocytosis, resulting in the restoration and maintenance of anti-inflammatory and tolerogenic milieu (4). On the contrary, delayed neutrophil apoptosis and/or impaired phagocytic clearance of apoptotic neutrophils by macrophages leads to prolonged inflammation that is the hallmark of a number of diseases (5-8). Hence, facilitation of neutrophil apoptosis and phagocytic clearance of apoptotic neutrophils by macrophages is an important strategy to limit inflammation-mediated tissue damage to restore tissue homeostasis (9 -11).Macrophages undergo phenotypic changes to adapt to the transition from proinflammatory to anti-inflammatory states of wou...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

See 1 more Smart Citation

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

He¹,

Zhang²,

Tighe³

et al. 2013

Journal of Biological Chemistry

115

118

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“…After 72 h of incubation, 1 μCi of [ 3 H]-thymidine (Amersham Bioscience, Little Chalfont, UK) was added per well and incubated for another 18 h. The cells were then harvested and the radioactivity incorporated was measured by liquid scintillation counting in a plate reader (Wallace 1450 Microbeta Plus; Wallace Oya, Turku, Finland) [26,29,30] .…”

Section: Proliferation Assay With Incorporation Of [ 3 H]-thymidinementioning

confidence: 99%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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Objective: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). Methods: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBP_p161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. Results: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with β₂-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The β₂-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. Conclusions: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

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“…AM’s anti-inflammatory action has been demonstrated in a number of studies, in which transplanted cryopreserved AM induces apoptosis of neutrophils, 63,64 monocytes, and macrophages 65 ; reduces infiltration of neutrophils, 63,66 macrophages 67,68 and lymphocytes 69 ; and promotes polarization of M2 macrophages. 70 …”

Section: Molecular Mechanism Of Amniotic Membrane’s Therapeutic mentioning

confidence: 99%

Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration

Tseng

Zhang

et al. 2016

The Ocular Surface

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Human limbal palisades of Vogt are the ideal site for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation in limbal stroma is common manifestation of limbal stem cell (SC) deficiency and presents as a threat to the success of transplanted limbal epithelial SCs. This pathologic process can be overcome by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring and anti-angiogenic action to promote wound healing. To determine how AM might exert anti-inflammation and promote regeneration, we have purified a novel matrix, HC-HA/PTX3, responsible for the efficacy of AM efficacy. HC-HA complex is covalently formed by hyaluronan (HA) and heavy chain 1 (HC1) of inter-α-trypsin inhibitor by the catalytic action of tumor necrosis factor-stimulated gene-6 (TSG-6) and are tightly associated with pentraxin 3 (PTX3) to form HC-HA/PTX3. In vitro reconstitution of the limbal niche can be established by reunion between limbal epithelial progenitors and limbal niche cells on different substrates. In 3-dimensional Matrigel, clonal expansion indicative of SC renewal is correlated with activation of canonical Wnt signaling and suppression of canonical BMP signaling. In contrast, SC quiescence can be achieved in HC-HA/PTX3 by activation of canonical BMP signaling and non-canonical planar cell polarity (PCP) Wnt signaling, but suppression of canonical Wnt signaling. HC-HA/PTX3 is a novel matrix mitigating nonresolving inflammation and restoring SC quiescence in the niche for various applications in regenerative medicine.

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Amniotic Membrane Induces Peroxisome Proliferator-Activated Receptor-γ Positive Alternatively Activated Macrophages

Cited by 30 publications

References 70 publications

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration

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