Both MC5r and A2Ar Are Required for Protective Regulatory Immunity in the Spleen of Post–Experimental Autoimmune Uveitis in Mice

Lee, Darren J.; Taylor, Andrew W.

doi:10.4049/jimmunol.1300182

Cited by 59 publications

(125 citation statements)

References 50 publications

(64 reference statements)

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“…All five of the melanocortin receptors have anti-inflammatory activities (Caruso et al, 2007; Catania et al, 2004; Catania et al, 2010; Getting et al, 2008; Lee and Taylor, 2013; Li and Taylor, 2008). It seems plausible that the hypometabolism/hypothermia/hypotension effects are part of a physiologic response to limit stress/inflammation and increase survival.…”

Section: Discussionmentioning

confidence: 99%

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Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

et al. 2014

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Summary The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists and MTII selectively activated arcuate nucleus dopaminergic neurons; these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress.

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Section: Discussionmentioning

confidence: 99%

“…Genetic variation in MC3R may contribute to human obesity (Feng et al, 2005; Renquist et al, 2011). MC5R regulates exocrine secretion (Chen et al, 1997) and inflammation (Lee and Taylor, 2013). …”

Section: Introductionmentioning

confidence: 99%

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

et al. 2014

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“…Inflammation in C57BL/6 J mice resolves at 75–90 days, at which time post-EAU regulatory immunity is found in the spleen9. An important role of post-EAU regulatory immunity is to prevent a memory immune response to ocular auto-antigen, and can be transferred to suppress EAU in recipient mice9101112. Mice that have recovered from EAU and have regulatory immunity show a naïve immune response when reimmunized for EAU13.…”

mentioning

confidence: 99%

“…Post-EAU regulatory immunity is also dependent on the expression of the Melanocortin 5 receptor (MC5r)101113, one of the melanocortin receptors for the immunomodulating neuropeptide, alpha-melanocyte stimulating hormone (α-MSH)1516. The neuropeptide, α-MSH, is constitutively expressed in the healthy ocular microenvironment, and inhibits macrophages and dendritic cell pro-inflammatory signaling and function1718.…”

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confidence: 99%

MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

Lee

Preble

Lee

et al. 2016

Sci Rep

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Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients.

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“…Thus, A 2A adenosine receptor activation on T cells was associated with antigen-presenting cells (APC) induction and activation of Tregs (regulatory T cells), which mediate a postexperimental autoimmune uveoretinitis regulatory immune response to ocular autoantigens protecting from recurrence of uveitis [56]. …”

Section: Adenosine Receptorsmentioning

confidence: 99%

Purinergic Receptors in Ocular Inflammation

Guzmán-Aránguez

Gasull

Diebold

et al. 2014

Mediators of Inflammation

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Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A), and P1,P5-diadenosine pentaphosphate (Ap5A) are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (CF101) have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases) can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.

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Both MC5r and A2Ar Are Required for Protective Regulatory Immunity in the Spleen of Post–Experimental Autoimmune Uveitis in Mice

Cited by 59 publications

References 50 publications

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

Purinergic Receptors in Ocular Inflammation

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