PMC:7572937 / 33513-38248 JSONTXT

{"project":"MyTest","denotations":[{"id":"33082511-21548792-29997638","span":{"begin":943,"end":945},"obj":"21548792"},{"id":"33082511-16723446-29997638","span":{"begin":943,"end":945},"obj":"16723446"},{"id":"33082511-27072607-29997638","span":{"begin":943,"end":945},"obj":"27072607"},{"id":"33082511-31272712-29997638","span":{"begin":943,"end":945},"obj":"31272712"},{"id":"33082511-21228377-29997638","span":{"begin":943,"end":945},"obj":"21228377"},{"id":"33082511-23012360-29997638","span":{"begin":943,"end":945},"obj":"23012360"},{"id":"33082511-31272712-29997639","span":{"begin":1130,"end":1132},"obj":"31272712"},{"id":"33082511-23645879-29997640","span":{"begin":1133,"end":1136},"obj":"23645879"},{"id":"33082511-25277308-29997640","span":{"begin":1133,"end":1136},"obj":"25277308"},{"id":"33082511-24790856-29997640","span":{"begin":1133,"end":1136},"obj":"24790856"},{"id":"33082511-30419240-29997640","span":{"begin":1133,"end":1136},"obj":"30419240"},{"id":"33082511-21548792-29997641","span":{"begin":1667,"end":1670},"obj":"21548792"},{"id":"33082511-16723446-29997642","span":{"begin":1671,"end":1673},"obj":"16723446"},{"id":"33082511-21548792-29997643","span":{"begin":2041,"end":2043},"obj":"21548792"},{"id":"33082511-25146982-29997644","span":{"begin":2157,"end":2160},"obj":"25146982"},{"id":"33082511-29643724-29997645","span":{"begin":2933,"end":2937},"obj":"29643724"},{"id":"33082511-16723446-29997646","span":{"begin":3088,"end":3090},"obj":"16723446"},{"id":"33082511-24790856-29997647","span":{"begin":3217,"end":3220},"obj":"24790856"},{"id":"33082511-30419240-29997648","span":{"begin":3814,"end":3817},"obj":"30419240"},{"id":"33082511-27072607-29997649","span":{"begin":3924,"end":3927},"obj":"27072607"},{"id":"33082511-28892824-29997650","span":{"begin":3928,"end":3931},"obj":"28892824"},{"id":"33082511-27072607-29997651","span":{"begin":4080,"end":4082},"obj":"27072607"},{"id":"33082511-28892824-29997652","span":{"begin":4247,"end":4250},"obj":"28892824"},{"id":"33082511-30419240-29997653","span":{"begin":4731,"end":4734},"obj":"30419240"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"FPRs in the eye\nThe eye is an organ of the visual system. The structure of the eye evolved anatomically and immunologically to protect visual function81. Significantly, the exterior surface of the eye is in direct contact with the external environment and encounters an enormous amount of immunogens. The immune response in the eye is strictly regulated to maintain the transparency of the cornea. The ocular mucosal surface includes the cornea and the conjunctiva. Tear film protects these mucosal surfaces, and neural inputs from the cornea and conjunctiva regulate the production of tears. Tears contain various protective substances, such as mucin produced by goblet cells and immunoglobulins produced by plasma cells81.\nFPRs are expressed on various cell types in the ocular region, such as corneal endothelial cells, corneal epithelial cells, conjunctival goblet cells, retinal microglia, retinal pigment cells, and lens epithelial cells94–99. Additionally, various FPR-related ocular pathologies exist, such as retinal degeneration, uveitis, polypoidal choroidal vasculopathy, corneal neovascularization, and ocular allergy97,100–103. However, here, we only discuss the role of FPRs in the cornea and conjunctiva as ocular mucosal surfaces. The cornea is located at the anterior aspect of the eye and passes light to the lens. The immune response in the cornea is unreactive compared to that in the conjunctiva, because inflammation of the cornea can affect its transparency104. FPR2 is expressed on the corneal endothelium and epithelium, and the functional activity of FPR2 in those regions has been indirectly confirmed by effects of the FPR2 antagonist WRW494,95. The cornea is a transplantable tissue, and there are several reports that the ligands of FPR2, including LXA4 and RvD1, can be beneficial during corneal transplantation. LXA4 promotes the proliferation of human corneal endothelial cells, and when added to Optisol-GS, which is the pretransplant storage fluid for corneas, LXA4 reduces corneal endothelial cell damage94. RvD1 reduces allograft mortality during corneal transplantation by regulating DC-mediated inflammatory responses105. Although RvD1 promotes corneal wound healing, it is not clear whether FPR2 mediates the effect of RvD1 in vivo.\nDiabetes is a representative metabolic disease with ocular complications. Diabetic patients show impaired corneal wound healing because of corneal epithelium and nerve defects. RvD1 can improve corneal epithelial regeneration in diabetic mice. RvD1 acts via the following mechanisms: increased expression of proliferation-related molecules (Ki67 and SIRT1), EGFR activation, decreased inflammatory cytokine (TNF-α, IL-1β) production, decreased expression of ROS-generating enzymes (NOX2 and NOX3), and upregulated expression of antioxidant genes (Nrf2, MnSOD, and HO-1). WRW4, the FPR2 antagonist, significantly blocks these various therapeutic effects of RvD1106. Another FPR2 ligand, LL-37, also promotes corneal epithelial cell migration in a PTX- and FPR2-sensitive manner and facilitates corneal wound healing95. Regarding SAA, the expression of Saa1,3 was increased with the expression of Fpr2 in a corneal neovascularization mouse model102. This pattern implies that SAA-FPR2 plays a role in this condition.\nThe conjunctiva is a mucosal tissue composed of three layers: the conjunctival epithelial layer, goblet cell layer, and lamina propria. The lamina propria is the site where immune cells reside and produces immunoregulatory factors. In the conjunctiva, several immune responses, such as antigen processing, cell-mediated immunity, and hypersensitivity, occur104. The conjunctiva exhibits basal expression of FPR1 and FPR2, and FPR1 and FPR2 expression is elevated in the setting of inflammation, such as in allergic conditions103. FPR2 is expressed on conjunctival goblet cells and increases mucin production by recognizing LXA4 and RvD196,107. Intracellular calcium influx is directly related to glycoconjugate secretion, and the LXA4-FPR2 axis can promote mucin secretion via calcium influx96. Various downstream signaling molecules of FPR2 affect calcium influx, which shows that FPR2 signaling and homeostasis of the ocular environment are closely related107.\nOne report addressed AnxA1 and FPRs in the case of ocular allergy. Upon the induction of allergic conjunctivitis in mice, FPR1 and FPR2 expression was increased. Interestingly, AnxA1 knockout mice showed a significant increase in FPR2 expression. AnxA1 is an anti-inflammatory mediator that decreases granulocyte infiltration and proinflammatory cytokine production in allergic conjunctivitis. These protective effects were diminished by treatment with Boc2, a pan-FPR antagonist103."}

{"project":"2_test","denotations":[{"id":"33082511-21548792-29997638","span":{"begin":943,"end":945},"obj":"21548792"},{"id":"33082511-16723446-29997638","span":{"begin":943,"end":945},"obj":"16723446"},{"id":"33082511-27072607-29997638","span":{"begin":943,"end":945},"obj":"27072607"},{"id":"33082511-31272712-29997638","span":{"begin":943,"end":945},"obj":"31272712"},{"id":"33082511-21228377-29997638","span":{"begin":943,"end":945},"obj":"21228377"},{"id":"33082511-23012360-29997638","span":{"begin":943,"end":945},"obj":"23012360"},{"id":"33082511-31272712-29997639","span":{"begin":1130,"end":1132},"obj":"31272712"},{"id":"33082511-23645879-29997640","span":{"begin":1133,"end":1136},"obj":"23645879"},{"id":"33082511-25277308-29997640","span":{"begin":1133,"end":1136},"obj":"25277308"},{"id":"33082511-24790856-29997640","span":{"begin":1133,"end":1136},"obj":"24790856"},{"id":"33082511-30419240-29997640","span":{"begin":1133,"end":1136},"obj":"30419240"},{"id":"33082511-21548792-29997641","span":{"begin":1667,"end":1670},"obj":"21548792"},{"id":"33082511-16723446-29997642","span":{"begin":1671,"end":1673},"obj":"16723446"},{"id":"33082511-21548792-29997643","span":{"begin":2041,"end":2043},"obj":"21548792"},{"id":"33082511-25146982-29997644","span":{"begin":2157,"end":2160},"obj":"25146982"},{"id":"33082511-29643724-29997645","span":{"begin":2933,"end":2937},"obj":"29643724"},{"id":"33082511-16723446-29997646","span":{"begin":3088,"end":3090},"obj":"16723446"},{"id":"33082511-24790856-29997647","span":{"begin":3217,"end":3220},"obj":"24790856"},{"id":"33082511-30419240-29997648","span":{"begin":3814,"end":3817},"obj":"30419240"},{"id":"33082511-27072607-29997649","span":{"begin":3924,"end":3927},"obj":"27072607"},{"id":"33082511-28892824-29997650","span":{"begin":3928,"end":3931},"obj":"28892824"},{"id":"33082511-27072607-29997651","span":{"begin":4080,"end":4082},"obj":"27072607"},{"id":"33082511-28892824-29997652","span":{"begin":4247,"end":4250},"obj":"28892824"},{"id":"33082511-30419240-29997653","span":{"begin":4731,"end":4734},"obj":"30419240"}],"text":"FPRs in the eye\nThe eye is an organ of the visual system. The structure of the eye evolved anatomically and immunologically to protect visual function81. Significantly, the exterior surface of the eye is in direct contact with the external environment and encounters an enormous amount of immunogens. The immune response in the eye is strictly regulated to maintain the transparency of the cornea. The ocular mucosal surface includes the cornea and the conjunctiva. Tear film protects these mucosal surfaces, and neural inputs from the cornea and conjunctiva regulate the production of tears. Tears contain various protective substances, such as mucin produced by goblet cells and immunoglobulins produced by plasma cells81.\nFPRs are expressed on various cell types in the ocular region, such as corneal endothelial cells, corneal epithelial cells, conjunctival goblet cells, retinal microglia, retinal pigment cells, and lens epithelial cells94–99. Additionally, various FPR-related ocular pathologies exist, such as retinal degeneration, uveitis, polypoidal choroidal vasculopathy, corneal neovascularization, and ocular allergy97,100–103. However, here, we only discuss the role of FPRs in the cornea and conjunctiva as ocular mucosal surfaces. The cornea is located at the anterior aspect of the eye and passes light to the lens. The immune response in the cornea is unreactive compared to that in the conjunctiva, because inflammation of the cornea can affect its transparency104. FPR2 is expressed on the corneal endothelium and epithelium, and the functional activity of FPR2 in those regions has been indirectly confirmed by effects of the FPR2 antagonist WRW494,95. The cornea is a transplantable tissue, and there are several reports that the ligands of FPR2, including LXA4 and RvD1, can be beneficial during corneal transplantation. LXA4 promotes the proliferation of human corneal endothelial cells, and when added to Optisol-GS, which is the pretransplant storage fluid for corneas, LXA4 reduces corneal endothelial cell damage94. RvD1 reduces allograft mortality during corneal transplantation by regulating DC-mediated inflammatory responses105. Although RvD1 promotes corneal wound healing, it is not clear whether FPR2 mediates the effect of RvD1 in vivo.\nDiabetes is a representative metabolic disease with ocular complications. Diabetic patients show impaired corneal wound healing because of corneal epithelium and nerve defects. RvD1 can improve corneal epithelial regeneration in diabetic mice. RvD1 acts via the following mechanisms: increased expression of proliferation-related molecules (Ki67 and SIRT1), EGFR activation, decreased inflammatory cytokine (TNF-α, IL-1β) production, decreased expression of ROS-generating enzymes (NOX2 and NOX3), and upregulated expression of antioxidant genes (Nrf2, MnSOD, and HO-1). WRW4, the FPR2 antagonist, significantly blocks these various therapeutic effects of RvD1106. Another FPR2 ligand, LL-37, also promotes corneal epithelial cell migration in a PTX- and FPR2-sensitive manner and facilitates corneal wound healing95. Regarding SAA, the expression of Saa1,3 was increased with the expression of Fpr2 in a corneal neovascularization mouse model102. This pattern implies that SAA-FPR2 plays a role in this condition.\nThe conjunctiva is a mucosal tissue composed of three layers: the conjunctival epithelial layer, goblet cell layer, and lamina propria. The lamina propria is the site where immune cells reside and produces immunoregulatory factors. In the conjunctiva, several immune responses, such as antigen processing, cell-mediated immunity, and hypersensitivity, occur104. The conjunctiva exhibits basal expression of FPR1 and FPR2, and FPR1 and FPR2 expression is elevated in the setting of inflammation, such as in allergic conditions103. FPR2 is expressed on conjunctival goblet cells and increases mucin production by recognizing LXA4 and RvD196,107. Intracellular calcium influx is directly related to glycoconjugate secretion, and the LXA4-FPR2 axis can promote mucin secretion via calcium influx96. Various downstream signaling molecules of FPR2 affect calcium influx, which shows that FPR2 signaling and homeostasis of the ocular environment are closely related107.\nOne report addressed AnxA1 and FPRs in the case of ocular allergy. Upon the induction of allergic conjunctivitis in mice, FPR1 and FPR2 expression was increased. Interestingly, AnxA1 knockout mice showed a significant increase in FPR2 expression. AnxA1 is an anti-inflammatory mediator that decreases granulocyte infiltration and proinflammatory cytokine production in allergic conjunctivitis. These protective effects were diminished by treatment with Boc2, a pan-FPR antagonist103."}