Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

Davis, Reema B.; Kechele, Daniel O.; Blakeney, Elizabeth S; Pawlak, J; Caron, Kathleen M.

doi:10.1172/jci.insight.92465

Cited by 60 publications

(74 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Selective lymphatic deletion of calcitonin receptor-like receptor (CLR), the core subunit of the canonical CGRP receptor (CLR/RAMP1) and the 2 adrenomedullin receptors (AM1 and AM2), has been shown in mice to exacerbate intestinal inflammation and impair lipid absorption after acute mucosal injury. 113 In an extension of these studies, the same group recently showed that this selective deletion of CLR in the lymphatics resulted in disorganized and reduced mucosal and submucosal innervation and inefficient absorption of dietary fat under conditions of a high-fat diet. These findings, together with the observation that mice with genetic loss of the CGRP coreceptor RAMP1 have mucosal and submucosal innervation deficits, suggest that CRL, and perhaps CGRP receptors in particular, may play a regulatory role in the neurolymphocrine axis that regulates intestinal lipid absorption.…”

Section: -Antimigraine and Gi Sites Of Action Of Cgrp Modulators At Cmentioning

confidence: 99%

“…Selective lymphatic deletion of calcitonin receptor‐like receptor (CLR), the core subunit of the canonical CGRP receptor (CLR/RAMP1) and the 2 adrenomedullin receptors (AM1 and AM2), has been shown in mice to exacerbate intestinal inflammation and impair lipid absorption after acute mucosal injury . In an extension of these studies, the same group recently showed that this selective deletion of CLR in the lymphatics resulted in disorganized and reduced mucosal and submucosal innervation and inefficient absorption of dietary fat under conditions of a high‐fat diet.…”

Section: Comparing the Cgrp Antibodies Clinicallymentioning

confidence: 99%

See 1 more Smart Citation

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

2019

View full text Add to dashboard Cite

Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain‐producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP‐RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo‐controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11C]MK‐4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP‐RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP‐RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood‐brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next‐generation small molecule CGRP‐RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP‐based therapeutic options for migraine patients.

show abstract

Section: -Antimigraine and Gi Sites Of Action Of Cgrp Modulators At Cmentioning

confidence: 99%

Section: Comparing the Cgrp Antibodies Clinicallymentioning

confidence: 99%

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

2019

View full text Add to dashboard Cite

show abstract

“…This process is mediated by Notch signaling, and the expression of the Notch ligand delta-like 4 requires activation of VEGFR3 and VEGFR2 (Bernier-Latmani et al, 2015). Besides VEGF-C, adrenomedullin signaling through its receptor complex, calcitonin receptor-like (CRL) receptor, is also an important mediator for lymphangiogenesis during development and maintenance in adult mice (Hoopes et al, 2012;Davis et al, 2017). Lymphatic Calcrl (encoding CRL) deletion in adult mice compromises systemic lymphatic function, induces inflammation and lymphatic dilation in the gut, reduces lacteal proliferation, and impairs lipid absorption (Davis et al, 2017).…”

Section: Lymphatics In the Regulation Of Lipid Mobilizationmentioning

confidence: 99%

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

et al. 2020

View full text Add to dashboard Cite

Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and postassembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health.

show abstract

“…Other models involving gene deletions or implantation of cells from human lymphatic malformations have been used to mimic human lymphatic disorders (37)(38)(39)(40). These models have proven useful in characterizing these conditions but are yet to be used to study the regression of abnormal lymphatics.…”

Section: Attributes and Limitations Of The Ccsp/vegf-c Mouse Model Ofmentioning

confidence: 99%

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Bałuk¹,

Yao²,

Flores³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

Cited by 60 publications

References 50 publications

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Contact Info

Product

Resources

About