Retinoid Regulation of Ocular Surface Innate Inflammation

Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular surface retinoid axis, particularly immunomodulatory effects of retinoic acid (RA) and change in conjunctival myeloid cell number and phenotype in VAD. We discovered that ocular surface epithelial and myeloid cells express retinoid receptors. Both all trans- and 9-cis-RA suppressed production of dry eye relevant inflammatory mediators [interleukin(IL)-1β, IL-12, regulated upon activation, normal T cell expressed and secreted (RANTES)] by myeloid cells. Systemic VAD was associated with significant goblet cell loss and an increased number of CD45+ immune cells in the conjunctiva. MHCII−CD11b+ classical monocytes were significantly increased in the conjunctiva of VAD C57BL/6 and RXR-α mutated Pinkie strains. RNA seq revealed significantly increased expression of innate immune/inflammatory genes in the Pinkie conjunctiva. These findings indicate that retinoids are essential for maintaining a healthy, well-lubricated ocular surface and have immunomodulatory effects in the conjunctiva that are mediated in part via RXR-α signaling. Perturbation of the homeostatic retinoid axis could potentiate inflammation on the ocular surface.

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Mcl-1 in Transgenic Mice Promotes Survival in a Spectrum of Hematopoietic Cell Types and Immortalization in the Myeloid Lineage

Blood ◽

10.1182/blood.v92.9.3226 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3226-3239 ◽

Cited By ~ 109

Author(s):

Ping Zhou ◽

Liping Qian ◽

Christine K. Bieszczad ◽

Randolph Noelle ◽

Michael Binder ◽

...

Keyword(s):

Myeloid Cells ◽

Myeloid Cell ◽

Cell Types ◽

Cell Number ◽

Hematopoietic Cell ◽

Viable Cell Number ◽

Wide Range ◽

Transgenic Cells

Abstract Mcl-1 is a member of the Bcl-2 family that is expressed in early monocyte differentiation and that can promote viability on transfection into immature myeloid cells. However, the effects of Mcl-1 are generally short lived compared with those of Bcl-2 and are not obvious in some transfectants. To further explore the effects of this gene, mice were produced that expressed Mcl-1 as a transgene in hematolymphoid tissues. The Mcl-1 transgene was found to cause moderate viability enhancement in a wide range of hematopoietic cell types, including lymphoid (B and T) as well as myeloid cells at both immature and mature stages of differentiation. However, enhanced hematopoietic capacity in transgenic bone marrow and spleen was not reflected in any change in pool sizes in the peripheral blood. In addition, among transgenic cells, mature T cells remained long lived compared with B cells and macrophages could live longer than either of these. Interestingly, when hematopoietic cells were maintained in tissue culture in the presence of interleukin-3, Mcl-1 enhanced the probability of outgrowth of continuously proliferating myeloid cell lines. Thus, Mcl-1 transgenic cells remained subject to normal in vivo homeostatic mechanisms controlling viable cell number, but these constraints could be overridden under specific conditions in vitro. Within the organism, Bcl-2 family members may act at “viability gates” along the differentiation continuum, functioning as part of a system for controlled hematopoietic cell amplification. Enforced expression of even a moderate viability-promoting member of this family such as Mcl-1, within a conducive intra- and extracellular environment in isolation from normal homeostatic constraints, can substantially increase the probability of cell immortalization. © 1998 by The American Society of Hematology.

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Mcl-1 in Transgenic Mice Promotes Survival in a Spectrum of Hematopoietic Cell Types and Immortalization in the Myeloid Lineage

Blood ◽

10.1182/blood.v92.9.3226.421k49_3226_3239 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3226-3239 ◽

Cited By ~ 12

Author(s):

Ping Zhou ◽

Liping Qian ◽

Christine K. Bieszczad ◽

Randolph Noelle ◽

Michael Binder ◽

...

Keyword(s):

Myeloid Cells ◽

Myeloid Cell ◽

Cell Types ◽

Cell Number ◽

Hematopoietic Cell ◽

Viable Cell Number ◽

Wide Range ◽

Transgenic Cells

Mcl-1 is a member of the Bcl-2 family that is expressed in early monocyte differentiation and that can promote viability on transfection into immature myeloid cells. However, the effects of Mcl-1 are generally short lived compared with those of Bcl-2 and are not obvious in some transfectants. To further explore the effects of this gene, mice were produced that expressed Mcl-1 as a transgene in hematolymphoid tissues. The Mcl-1 transgene was found to cause moderate viability enhancement in a wide range of hematopoietic cell types, including lymphoid (B and T) as well as myeloid cells at both immature and mature stages of differentiation. However, enhanced hematopoietic capacity in transgenic bone marrow and spleen was not reflected in any change in pool sizes in the peripheral blood. In addition, among transgenic cells, mature T cells remained long lived compared with B cells and macrophages could live longer than either of these. Interestingly, when hematopoietic cells were maintained in tissue culture in the presence of interleukin-3, Mcl-1 enhanced the probability of outgrowth of continuously proliferating myeloid cell lines. Thus, Mcl-1 transgenic cells remained subject to normal in vivo homeostatic mechanisms controlling viable cell number, but these constraints could be overridden under specific conditions in vitro. Within the organism, Bcl-2 family members may act at “viability gates” along the differentiation continuum, functioning as part of a system for controlled hematopoietic cell amplification. Enforced expression of even a moderate viability-promoting member of this family such as Mcl-1, within a conducive intra- and extracellular environment in isolation from normal homeostatic constraints, can substantially increase the probability of cell immortalization. © 1998 by The American Society of Hematology.

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Vitamin A deficiency in mice causes a systemic expansion of myeloid cells

Blood ◽

10.1182/blood.v95.11.3349 ◽

2000 ◽

Vol 95 (11) ◽

pp. 3349-3356 ◽

Cited By ~ 98

Author(s):

Takeshi Kuwata ◽

I-Ming Wang ◽

Tomohiko Tamura ◽

Roshini M. Ponnamperuma ◽

Rachel Levine ◽

...

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Cell Population ◽

Vitamin A Deficiency ◽

Myeloid Cells ◽

Myeloid Cell ◽

Direct Result ◽

Essentially Normal ◽

Deficient Mice

Abstract To examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A–deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A–deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice. This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders.

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Vitamin A deficiency in mice causes a systemic expansion of myeloid cells

Blood ◽

10.1182/blood.v95.11.3349.011k46_3349_3356 ◽

2000 ◽

Vol 95 (11) ◽

pp. 3349-3356 ◽

Cited By ~ 5

Author(s):

Takeshi Kuwata ◽

I-Ming Wang ◽

Tomohiko Tamura ◽

Roshini M. Ponnamperuma ◽

Rachel Levine ◽

...

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Cell Population ◽

Vitamin A Deficiency ◽

Myeloid Cells ◽

Myeloid Cell ◽

Direct Result ◽

Essentially Normal ◽

Deficient Mice

To examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A–deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A–deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice. This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders.

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Immunomodulatory Effects of Topical Ophthalmic Tofacitinib (Cp-690,550) in Dry Eye Disease

US Ophthalmic Review ◽

10.17925/usor.2014.07.01.12 ◽

2014 ◽

Vol 07 (01) ◽

pp. 12

Author(s):

Jing-Feng Huang ◽

Keyword(s):

Dry Eye ◽

Ocular Surface ◽

Janus Kinase ◽

Immunomodulatory Activity ◽

Immunomodulatory Effects ◽

Signal Transducers ◽

The Us ◽

Ocular Surface Health ◽

Surface Inflammation ◽

Ocular Surface Inflammation

Ocular surface inflammation is thought to play a key role in dry eye pathogenesis and clinical manifestation. Multiple inflammatory cytokines signal through intracellular janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. Tofacitinib (CP-690,550), a potent and selective inhibitor of JAKs, has been approved for the treatment of rheumatoid arthritis in the US and is in clinical development for the treatment of other autoimmune diseases. Topical ophthalmic tofacitinib was evaluated and has shown immunomodulatory activity in reducing ocular surface inflammation in dry eye, thus, has the potential to improve ocular surface health in dry eye.

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Should we care about the ocular surface in the anophthalmic patient?

European Journal of Ophthalmology ◽

10.1177/11206721211048803 ◽

2021 ◽

pp. 112067212110488

Author(s):

Giulio Volpe ◽

Maria De Piano ◽

Giacomilde Mazzone ◽

Alessandra Micera ◽

Stefano Bonini ◽

...

Keyword(s):

Oxidative Stress ◽

Dry Eye ◽

Ocular Surface ◽

Bulbar Conjunctiva ◽

Type I ◽

Ocular Prosthesis ◽

Fellow Eye ◽

Markers Of Inflammation ◽

Conjunctival Inflammation ◽

Anophthalmic Socket

Purpose: To assess clinical and biomolecular changes of the conjunctival epithelium in anophthalmic patients wearing an ocular prosthesis. Methods: Thirty-five unilateral anophthalmic patients were enrolled. Patients with blepharitis, lid abnormalities, and topical/systemic medication affecting the ocular surface were excluded. Symptom Assessment in Dry Eye (SANDE) questionnaire and tear function test (Schirmer Test Type I) were recorded. Conjunctival inflammation and meibomian gland dysfunction (MGD) were graded in the anophthalmic side and fellow eye. Impression cytology sampling of the upper, lower tarsal, and posterior/bulbar conjunctiva from the anophthalmic socket were collected and compared to healthy controls. Results: Patients had significantly higher SANDE ( p < 0.001), Schirmer I test ( p = 0.004), conjunctival inflammation ( p < 0.001), and MGD scores ( p < 0.001) on the anophthalmic side compared to the fellow eye. Mucin 5AC, inflammatory markers (MMP-9, ICAM-1) expression ( p < 0.001), and response to oxidative stress (NRF2-KEAP1 signaling pathway) ( p < 0.05) were significantly upregulated in the posterior conjunctival surface in the anophthalmic socket. Conclusions: Anophthalmic patients complained of more pronounced dry eye symptoms and presented more significant signs of inflammation and MGD on the anophthalmic side. The bulbar conjunctiva, behind the prosthesis, showed more significant hyperexpression of mucins, markers of inflammation, and increased response to oxidative stress compared to the tarsal conjunctiva. Patients wearing ocular prosthesis had signs of inflammation resembling dry eye disease.

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