scholarly journals Tumor-Associated Macrophages in Vestibular Schwannoma and Relationship to Hearing

OTO Open ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 2473974X2110591
Author(s):  
Eric Nisenbaum ◽  
Carly Misztal ◽  
Mikhaylo Szczupak ◽  
Torin Thielhelm ◽  
Stefanie Peña ◽  
...  
Keyword(s):  
Vestibular Schwannoma ◽  
Macrophage Polarization ◽  
Tertiary Care ◽  
Vestibular Schwannomas ◽  
In Vitro Assays ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Monocyte Migration ◽  
Hearing Outcomes

Objective (1) Characterize the distribution of M1 and M2 macrophages in vestibular schwannomas by hearing status. (2) Develop assays to assess monocyte migration and macrophage polarization in cocultures with vestibular schwannoma cells. Study Design Basic and translational science. Setting Tertiary care center. Methods A retrospective chart review of 30 patients with vestibular schwannoma (VS) was performed. Patients were stratified into serviceable and unserviceable hearing groups. Immunohistochemistry for CD80+ M1 and CD163+ M2 macrophages was conducted. Primary VS cultures (n = 4) were developed and cocultured with monocytes. Immunohistochemistry for macrophage markers was performed to assess monocyte migration and macrophage polarization. Results Although tumors associated with unserviceable hearing had higher levels of CD80 and CD163 than those with serviceable hearing, the relationship was only significant with CD163 ( P = .0161). However, CD163 level did not remain a significant predictor variable associated with unserviceable hearing on multivariate analysis when adjusted for other variables. In vitro assays show that VS cells induced monocyte migration and polarization toward CD80+ M1 or CD163+ M2 macrophage phenotypes, with qualitative differences in CD163+ macrophage morphologies between serviceable and unserviceable hearing groups. Conclusion Vestibular schwannomas express varying degrees of CD80+ M1 and CD163+ M2 macrophages. We present evidence that higher expression of CD163+ may contribute to poorer hearing outcomes in patients with VS. We also describe in vitro assays in a proof-of-concept investigation that VS cells can initiate monocyte migration and macrophage polarization. Future investigations are warranted to explore the relationships between tumor, macrophages, secreted cytokines, and hearing outcomes in patients with VS.

scholarly journals TMIC-51. GBP1 RECRUITS MACROPHAGES TO PROMOTE GLIOBLASTOMA GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi259-vi259
Author(s):  
Lili Chen ◽  
Ming Li
Keyword(s):  
Macrophage Polarization ◽  
Tumor Development ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Orthotopic Mouse Model ◽  
Ccl2 Expression ◽  
Molecule Inhibitor ◽  
Signaling Axis ◽  
And Migration

Abstract Guanylate binding protein 1 (GBP1) is an interferon-inducible large GTPase which plays a key role in tumor development, but the molecular mechanism is poorly understood. Here we investigated whether GBP1 could influence the tumor microenvironment in glioblastoma, the most common and malignant brain tumor. We found that forced expression of GBP1 in glioblastoma cells induced macrophage polarization toward an M2 phenotype via upregulating Chemokine (C-C motif) ligand 2 (CCL2). CCL2 acted via its receptor C-C chemokine receptor 2 (CCR2) to enhance macrophage cell migration in vitro. The M2 macrophages in turn promoted glioblastoma cell proliferation and migration. The orthotopic mouse model showed that GBP1 recruited M2 macrophages into tumor to promote glioblastoma progression, and targeting CCL2/CCR2 signaling axis with a small molecule inhibitor RS504393 led to decreased macrophage attraction and M2 polarization and a significant tumor growth retardation and prolonged survival of tumor-bearing mice. Clinically, GBP1 expression positively correlated with M2 macrophage numbers and CCL2 expression in glioblastoma. Taken together, our results reveal that GBP1 modulates the tumor immune microenvironment through CCL2 induction to promote glioblastoma infiltrating growth, and targeting tumor-associated macrophages may represent a new therapeutic strategy against glioblastoma.

scholarly journals Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Senlin Zhao ◽  
Yushuai Mi ◽  
Bingjie Guan ◽  
Binbin Zheng ◽  
Ping Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
In Vitro Assays ◽  
Luciferase Reporter ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Premetastatic Niche ◽  
Niche Formation

Abstract Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

scholarly journals Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yohei Kawai ◽  
Yuji Narita ◽  
Aika Yamawaki-Ogata ◽  
Akihiko Usui ◽  
Kimihiro Komori
Keyword(s):  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Gene Expressions ◽  
Arginase 1 ◽  
M2 Macrophage Polarization

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

scholarly journals Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair

2021 ◽  
Author(s):  
Xinyun Han ◽  
Junxian Hu ◽  
Wenbo Zhao ◽  
Hongwei Lu ◽  
Jingjin Dai ◽  
...  
Keyword(s):  
Bone Repair ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Promising Alternative ◽  
Defect Repair ◽  
M2 Macrophage Polarization ◽  
Underlying Mechanisms ◽  
Main Regulator

Abstract Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear. In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. In summary, these findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

scholarly journals Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair

2021 ◽  
Author(s):  
Xinyun Han ◽  
Junxian Hu ◽  
Wenbo Zhao ◽  
Hongwei Lu ◽  
Jingjin Dai ◽  
...  
Keyword(s):  
Bone Repair ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Promising Alternative ◽  
Defect Repair ◽  
M2 Macrophage Polarization ◽  
Underlying Mechanisms ◽  
Main Regulator

Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear. In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. In summary, these findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

scholarly journals The Cholinergic Anti-Inflammatory Pathway Attenuates the Development of Atherosclerosis in Apoe-/- Mice through Modulating Macrophage Functions

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1150
Author(s):  
Zhengjiang Qian ◽  
Haiyang Yang ◽  
Hongchao Li ◽  
Chunhua Liu ◽  
Liang Yang ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
M2 Macrophage ◽  
Mouse Bone Marrow ◽  
M2 Macrophages ◽  
Inflammatory Pathway ◽  
Primary Mouse ◽  
Anti Inflammatory

(1) Background: The cholinergic anti-inflammatory pathway (CAP) has been implicated in the regulation of various diseases, including chronic inflammatory cardiovascular disorders such as atherosclerosis (AS). This study aims to explore the underlying regulatory mechanisms of CAP activity in the progression of AS. (2) Methods: The Apoe-/- mice were subjected to sham, bilateral cervical vagotomy surgery (VGX), and VGX supplemented with Gainesville Tokushima scientists (GTS)-21 (4 mg/kg/d) and then fed with a high-fat diet for 10 weeks. Atherosclerotic lesion size and inflammation levels were investigated by histology and inflammatory cytokines analysis. The blood M1/M2 macrophages were analyzed by flow cytometry. Primary mouse bone marrow-derived macrophages (BMDM), peritoneal macrophages, and RAW264.7 cells were treated with CAP agonists acetylcholine (Ach) and GTS-21 to study their effects on macrophage functions. (3) Results: Compared with the sham group, inhibition of CAP by the VGX resulted in growing aortic lipid plaque area, deteriorated inflammatory levels, and aberrant quantity of M1/M2 macrophages in Apoe-/- mice. However, these detrimental effects of VGX were significantly ameliorated by the reactivation of CAP through GTS-21 treatment. The in vitro study using macrophages revealed that stimulation with CAP agonists suppressed M1, but promoted M2 macrophage polarization through the upregulation of TNFAIP3 and phosphorylation STAT3 levels, respectively. Moreover, the activation of CAP inhibited the formation of macrophage foam cells in the peritoneal cavity by regulating genes related to cholesterol metabolism. (4) Conclusions: This study provides novel evidence and mechanisms that the CAP plays an important role in the regulation of AS development by controlling macrophage functions, implying a potential use of CAP activation as a therapeutic strategy for AS treatment.

871 In vitro immunoregulatory effect from cervical cancer derived mesenchymal stromal cells over molecules expression in monocyte derived macrophage polarization

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A923-A923
Author(s):  
Víctor Cortés-Morales ◽  
Juan Montesinos ◽  
Luis Chávez-Sánchez ◽  
Sandra Espíndola-Garibay ◽  
Alberto Monroy-García ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Macrophage Polarization ◽  
Induction Medium ◽  
M2 Macrophage ◽  
List Type ◽  
M2 Phenotype

BackgroundMacrophages are immunological cells that sense microenvironmental signals that may result in the polarized expression of either proinflammatory (M1) or anti-inflammatory (M2) phenotype.1 Macrophages M2 are present in tumoral microenvironment and their presence in patients with cervical cancer (CeCa) is related with less survival.2Mesenchymal Stromal Cells (MSCs) are also present in tumor microenvironment of cervical cancer (CeCa-MSC), which have shown immunoregulatory effects over CD8 T cells, decreasing their cytotoxic effect against tumoral cells.3 Interestingly, MSCs from bone marrow (BM-MSC) decrease M1 and increase M2 macrophage polarization in an in vitro coculture system.4 Macrophages and MSCs are present in microenvironment of cervical cancer, however it is unknown if MSCs play a role in macrophage polarization. In the present study, we have evaluated the immunoregulatory capacity of CeCa-MSCs to induce macrophage polarization.MethodsCD14 monocytes were isolated from peripheral blood and cultivated in the absence or presence of MSCs from BM, normal cervix (NCx) and CeCa. Two culture conditions were included, in the presence of induction medium to favors M1 (GM-CSF, LPS and IFNg) or M2 (M-CSF, IL-4 and IL-13) macrophage polarization. M1 (HLA-DR, CD80, CD86 and IFNg) or M2 (CD14, CD163, CD206, IDO and IL-10) macrophage molecular markers were evaluated by flow cytometry. Finally, we evaluated concentration of IL-10 and TNFa in conditioned medium form all coculture conditions.ResultsWe observed that CeCa-MSCs and BM-MSCs in presence of M1 induction medium, decreased M1 macrophage markers (HLA-II, CD80, CD86 and IFNg), and increase the expression of CD14 (M2 macrophage marker). Interestingly, in presence of M2 induction medium, BM-MSCs and CaCe-MSCs but not CxN-MSC increased CD163, CD206, IDO and IL-10 (M2 macrophage markers). We observed a decreased concentration of TNFa in the supernatant medium from all cocultures with MSCs, but only in presence of CeCa-MSCs, increased IL-10 concentration was detected in such cocultures.ConclusionsIn contrast to NCx-MSCs, CeCa-MSCs similarly to BM-MSCs have in vitro capacity to decrease M1 and increase M2 macrophage phenotype.AcknowledgementsAcknowledgments The authors are indebted to gratefully acknowledge to CONACYT (Grant No. 272793) and IMSS (Grant no. 1731) for support to Juan J. Montesinos research.ReferencesMartinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6-13.Petrillo M, Zannoni GF, Martinelli E, et al. Polarization of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One 2015;10: e0136654.Montesinos JJ, Mora-García Mde L, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev 2013;22:2508-2519.Vasandan AB, Jahnavi S, Shashank C. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016;6:38308.

scholarly journals Dietary Fucose Affects Macrophage Polarization and Reproductive Performance in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 855
Author(s):  
Ekaterina A. Litvinova ◽  
Victoria D. Bets ◽  
Natalya A. Feofanova ◽  
Olga V. Gvozdeva ◽  
Kseniya M. Achasova ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Reproductive Performance ◽  
Immune Status ◽  
Macrophage Polarization ◽  
Bacterial Species ◽  
Peritoneal Macrophages ◽  
M2 Macrophage ◽  
Female Mice ◽  
Intestinal Mucus

Intestinal mucus protects epithelial and immune cells from the gut resident microorganisms, and provides growth-promoting factors as mucus-derived O-glycans for beneficial bacteria. A lack of intestinal protective mucus results in changes in the commensal microflora composition, mucosal immune system reprogramming, and inflammation. Previous work has shown that fucose, the terminal glycan chain component of the intestinal glycoprotein Mucin2, and fucoidan polysaccharides have an anti-inflammatory effect in some mouse models of colitis. This study evaluates the effect of fucose on reproductive performance in heterozygous mutant Muc2 female mice. We found that even though Muc2+/− females are physiologically indistinguishable from C57Bl/6 mice, they have a significantly reduced reproductive performance upon dietary fucose supplementation. Metagenomic analysis reveals that the otherwise healthy wild-type siblings of Muc2−/− animals have reduced numbers of some of the intestinal commensal bacterial species, compared to C57BL/6 mice. We propose that the changes in beneficial microflora affect the immune status in Muc2+/− mice, which causes implantation impairment. In accordance with this hypothesis, we find that macrophage polarization during pregnancy is impaired in Muc2+/− females upon addition of fucose. Metabolic profiling of peritoneal macrophages from Muc2+/− females reveals their predisposition towards anaerobic glycolysis in favor of oxidative phosphorylation, compared to C57BL/6-derived cells. In vitro experiments on phagocytosis activity and mitochondrial respiration suggest that fucose affects oxidative phosphorylation in a genotype-specific manner, which might interfere with implantation depending on the initial status of macrophages. This hypothesis is further confirmed in BALB/c female mice, where fucose caused pregnancy loss and opposed implantation-associated M2 macrophage polarization. Taken together, these data suggest that intestinal microflora affects host immunity and pregnancy outcome. At the same time, dietary fucose might act as a differential regulator of macrophage polarization during implantation, depending on the immune status of the host.

847 Inflammasome activation in M2 macrophage restrain the immune suppressive function

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A900-A900
Author(s):  
Ronghua Zhang ◽  
Tienan Wang ◽  
Qing Lin
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Culture System ◽  
Cell Activation ◽  
Macrophage Polarization ◽  
Inflammasome Activation ◽  
M2 Macrophage ◽  
M1 Macrophage ◽  
Suppressive Phenotype

BackgroundMacrophage is an important component in tumor microenvironment (TME) and plays multiple roles in tumor initiation, progression and metastases. In response to various stimuli within TME, macrophage exhibits high level of functional heterogeneity. There are two distinct groups of macrophages: M1 macrophage exhibits pro-inflammatory phenotype with high levels of TNF-a, IL-6, and IL-1ß, while M2 macrophage displays immune suppressive phenotype with high levels of anti-inflammatory cytokines such as IL-10 and TGF-ß. In response to the M2 cytokines, myeloid cells within the TME further acquire higher expression of PD-L1 and thus inactivate T cells. M2 cytokines can also directly inhibit T cell activation. As a result, re-polarizing M2 macrophages becomes a key concept for cancer immunotherapy. The NLRP3 inflammasome is acquired by macrophages to fight against endogenous danger signals. Macrophage NLRP3 activation has been observed in several tumor models, but the function of NLRP3 on macrophage polarity remains controversial. Inflammasome activation with IL-1ß/IL-18 secretion was reported to promote M1 polarization. However, NLRP3 activation was also reported to promote M2 polarity through up-regulation of IL4 in asthma modelMethodsHere, we have established an in vitro human macrophage NLRP3 activation system (figure 1), coupled with M2 macrophage polarization assay, to dissect the role of NLRP3 in macrophage phenotype.ResultsOur results indicate that NLRP3 activation restrained M2 phenotype and further enhanced T cell activation in an M2/T cell co-culture system (figure 2).Abstract 847 Figure 1Inflammasome activation polarize M2 macrophage intUse LPS/ATP to stimulate NLRP3 in M2 macrophage and demonstrate NLRP3 activation could reduce CD163 and increase CD86Abstract 847 Figure 2Inflammasome in M2 rescue T cell activationestablish M2/T co-culture system in vitro to demonstrate M2 could suppress T activation while Inflammatory M2 could partial rescue the suppressive phenotypeConclusionsInflammasome could be the potential target for cancer by modulating T cell activation through macrophage polarization regulation

scholarly journals Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Nisha R. Dhanushkodi ◽  
Ruchi Srivastava ◽  
Pierre-Gregoire A. Coulon ◽  
Swayam Prakash ◽  
Soumyabrata Roy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Herpes Simplex Virus 1 ◽  
Cytokines And Chemokines ◽  
Latently Infected ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

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