RvE1 uses the LTB4 receptor BLT1 to increase [Ca2+]i and stimulate mucin secretion in cultured rat and human conjunctival goblet cells

Yang, Menglu; Lippestad, Marit; Hodges, Robin R.; Fjaervoll, Haakon; Fjaervoll, Ketil; Bair, Jeffery A.; Utheim, Tor Paaske; Serhan, Charles N.; Dartt, Darlene A.

doi:10.1016/j.jtos.2020.04.011

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…This study provides evidence that both RvE1 and RvD1 counterregulate the [Ca 2þ ] i increase triggered by LTB4 (Figure 7). Combining results from Yang et al 4 with those presented herein demonstrates that RvE1 employs two mechanisms to counterregulate the LTB4-stimulated response. First, RvE1 uses its receptor CMKLR1 to activate BARK1, which phosphorylates and down-regulates the BLT1 receptor, which prevented LTB4 from increasing [Ca 2þ ] i and stimulating secretion.…”

Section: Discussionsupporting

confidence: 80%

“…It was observed that either CMKLR1 or BLT1 knockdown decreases the RvE1-induced [Ca 2þ ] i increase as well as mucin secretion. 4 Decreasing the amount of the CMKLR1 did not fully reverse the effect of RvE1 on the increase in [Ca 2þ ] i , either because CMKLR1 was not completely depleted or activation of the BLT1 receptor by RvE1 could also contribute to the counterregulatory actions of RvE1 on LTB4einduced goblet cell response. Similarly to the lack of complete inhibition of RvE1 on the effect of LTB4, pharmacologic inhibition of the RvD1 receptor ALX/FPR2 did not fully reverse the RvD1-mediated decrease in LTB4 stimulation of the [Ca 2þ ] i .…”

Section: Discussionmentioning

confidence: 94%

“…Second, RvE1 interacts with the BLT1 receptor directly preventing LTB4 from activating it and thereby blocking the increase in [Ca 2þ ] i and stimulation of secretion. 4 In contrast to RvE1, RvD1 uses only one mechanism to counterregulate the LTB4-stimulated response in this tissue. RvD1 interacts with its receptor ALX/FPR2 to activate BARK1, which phosphorylates and down-regulates the BLT1 receptor.…”

Section: Discussionmentioning

confidence: 97%

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Resolvin E1 Reduces Leukotriene B4–Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells

Yang¹,

Bair²,

Hodges³

et al. 2020

The American Journal of Pathology

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Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense, whereas resolvins (Rvs) are produced during the resolution phase of inflammation. The authors determined the actions of both RvE1 and RvD1 on LTB4einduced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca 2þ ] ([Ca 2þ ] i ) and highe molecular-weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 minutes significantly blocked the LTB4einduced [Ca 2þ ] i increase. The actions of RvE1 on LTB4einduced [Ca 2þ ] i increase were reversed by siRNA for the RvE1 receptor, and the actions of RvD1 were reversed by an RvD1 receptor inhibitor. The RvE1 and RvD1 block of LTB4-stimulated increase in [Ca 2þ ] i was also reversed by an inhibitory peptide to b-adrenergic receptor kinase. LTB4 and block of the LTB4estimulated increase in [Ca 2þ ] i by RvE1 and RvD1 were partially mediated by the depletion of intracellular Ca 2þ stores. RvE1, but not RvD1, counterregulated the LTB4einduced highemolecular-weight glycoprotein secretion. Thus, both RvE1 and RvD1 receptors directly inhibit LTB4 by phosphorylating the LTB4 receptor using b adrenergic receptor kinase. RvE1 receptor counterregulates the LTB4einduced increase in [Ca 2þ ] i and secretion, whereas RvD1 receptor only counterregulates LTB4einduced [Ca 2þ ] i increase.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

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Resolvin E1 Reduces Leukotriene B4–Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells

Yang¹,

Bair²,

Hodges³

et al. 2020

The American Journal of Pathology

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“…Besides phagocytes, SPMs also display cell typespecific actions. For example, RvE1 activates both ERV1/ChemR23 and BLT1 on human conjunctival goblet cells to stimulate mucin secretion(158). 17R-RvD1 attenuates vascular smooth muscle cell migration via ALX/FPR2 and cAMP/PKA activity(159).…”

mentioning

confidence: 99%

Specialized pro-resolving mediator network: an update on production and actions

Chiang

Serhan

2020

Essays in Biochemistry

267

223

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Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2–3 years from human and preclinical animal studies, together with the structural–functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.

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“…Because of the structural similarity of 1 – 6 to RvE3 ( 8 ), we reasoned that algal oxylipins might also evoke anti-inflammatory and pro-resolving activities in mammals. This assumption was substantiated by previous observations demonstrating anti-inflammatory effects of raw extracts of C. closterium . , We therefore investigated compounds 1 – 6 for typical SPM bioactivities against human innate immune cells, focusing on their ability to regulate phagocytosis, efferocytosis, and chemotaxis in these cells. ,− ,, Among the novel algal oxylipins 1 – 6 , 1 and 2 mediated inflammation-resolving and anti-inflammatory features at concentrations comparable to RvE1 (Figures , , and S56).…”

Section: Resultsmentioning

confidence: 67%

14,17,18-Trihydroxy-Eicosatetraenoic Acid: A Novel Pro-Resolving Lipid Mediator from Marine Microalgae

Jagusch

Werner

Koenis

et al. 2021

ACS Pharmacol. Transl. Sci.

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Specialized pro-resolving mediators (SPMs) are enzymatically oxygenated derivatives of polyunsaturated fatty acids that function as central immunoregulators in mammals. Among them are resolvins (Rvs) that stimulate the clearance of harmful stimuli and limit pro-inflammatory processes. Because of their beneficial features and their high potency, SPMs are promising molecules for anti-inflammatory therapy. Besides mammals, also marine algae form lipid mediators such as prostaglandins and leukotrienes. In particular, microalgae are attractive candidates for the production of bioactive high-value metabolites. Here, we identified the diatom Cylindrotheca closterium as a prolific producer of SPMs. The diatom forms RvE3 and novel structurally related eicosanoids, including 14S/R,17R,18R-trihydroxy-eicosatetraenoic acid, which displays inflammation-resolving and anti-inflammatory bioactivities. This pro-resolving compound might enable advancements in anti-inflammatory therapy in mammals.

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RvE1 uses the LTB4 receptor BLT1 to increase [Ca2+]i and stimulate mucin secretion in cultured rat and human conjunctival goblet cells

Cited by 13 publications

References 29 publications

Resolvin E1 Reduces Leukotriene B4–Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells

Resolvin E1 Reduces Leukotriene B4–Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells

Specialized pro-resolving mediator network: an update on production and actions

14,17,18-Trihydroxy-Eicosatetraenoic Acid: A Novel Pro-Resolving Lipid Mediator from Marine Microalgae

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