Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

Jacob, Fenila; Novo, Claudina Pérez; Bachert, Claus; Crombruggen, Koen Van

doi:10.1007/s11302-013-9357-4

Cited by 198 publications

(174 citation statements)

References 235 publications

(316 reference statements)

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“…In addition, with aging, the vascular phenotype makes a proinflammatory shift that contributes to endothelial dysfunction (46). As demand for insulin increases with age, beta cells also cosecrete more ATP and other molecules that are potentially proinflammatory and that stimulate cytokine secretion and innate immune responses (47)(48)(49). The fibrosis associated with blood vessels in the aged islet likely diminishes hormone diffusion through the interstitial space and disrupts hormone release into the circulation (35), delaying insulin delivery to target tissues and causing the fragile glucose tolerance we observed in aged mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Young capillary vessels rejuvenate aged pancreatic islets

Almaça

Molina

Drigo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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Pancreatic islets secrete hormones that play a key role in regulating blood glucose levels (glycemia). Age-dependent impairment of islet function and concomitant dysregulation of glycemia are major health threats in aged populations. However, the major causes of the age-dependent decline of islet function are still disputed. Here we demonstrate that aging of pancreatic islets in mice and humans is notably associated with inflammation and fibrosis of islet blood vessels but does not affect glucose sensing and the insulin secretory capacity of islet beta cells. Accordingly, when transplanted into the anterior chamber of the eye of young mice with diabetes, islets from old mice are revascularized with healthy blood vessels, show strong islet cell proliferation, and fully restore control of glycemia. Our results indicate that beta cell function does not decline with age and suggest that islet function is threatened by an age-dependent impairment of islet vascular function. Strategies to mitigate age-dependent dysregulation in glycemia should therefore target systemic and/or local inflammation and fibrosis of the aged islet vasculature.A ging leads to progressive decline of various homeostatic processes in mammals, including a deteriorating regulation of blood glucose levels. Pancreatic islets are small organs composed of endocrine cells that secrete the major hormones insulin, glucagon, and somatostatin, which play a key role in regulating blood glucose levels. Age-dependent dysfunction of islets and the concomitant dysregulation of blood glucose levels increase the risk for type 2 diabetes (1), which in turn contributes to other age-related chronic diseases. In general, it has been assumed that aging causes an intrinsic dysfunction of the insulin-secreting beta cells through reduced proliferative capacity and/or defective insulin secretion (1-9). However, there have been numerous reports that age-dependent impairment of glucose homeostasis is not just a result of intrinsic, age-dependent dysfunction of islets but is also caused by systemic factors. For example, islet function may be compromised by age-related increases in adiposity (10, 11) and by bloodborne factors (12), or it could be affected indirectly by agerelated deficiencies in vascular remodeling (13). Thus, the replicative decline of old pancreatic beta cells can be attributed to systemic factors (12). Recent studies identified factors present in young blood that reverse age-related cognitive impairments and induce vascular remodeling and regeneration in the brain and skeletal muscle (14-16), but so far it has not been feasible to discriminate systemic influences from aging factors intrinsic to islet endocrine cells. Here we address the long-standing question of whether the age-dependent impairment of glucose homeostasis is caused by intrinsic, age-dependent dysfunction of islets or by systemic aging factors.Our strategy to discern age-related intrinsic changes in islet function was to study islets from young mature (2 mo) and aged (18 mo) mice and to fol...

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Section: Discussionmentioning

confidence: 99%

Young capillary vessels rejuvenate aged pancreatic islets

Almaça

Molina

Drigo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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“…5,14 Danger-associated molecular patterns can initiate and prolong immune responses in an infection-free environment. 15 ATP can be liberated after necrosis or necroptosis of cells.…”

Section: Atp and Adenosinementioning

confidence: 99%

Danger Signals From ATP and Adenosine in Pregnancy and Preeclampsia

et al. 2014

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“…P2X receptor involvement in inflammation also occurs in irritable bowel syndrome [6,7], lung injury and fibrosis [8,9], systemic inflammation [10], arthritis [11], fever [12], and rhinosinusitis [13]. Purinergic signalling in different inflammatory cells involves purinoceptor responses in immune cells (see [14]). Microglia are immune cells in the central nervous system (CNS) [15].…”

Section: Introductionmentioning

confidence: 99%

P2X ion channel receptors and inflammation

Burnstock

2016

Purinergic Signalling

182

153

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Neuroinflammation limits tissue damage in response to pathogens or injury and promotes repair. There are two stages of inflammation, initiation and resolution. P2X receptors are gaining attention in relation to immunology and inflammation. The P2X7 receptor in particular appears to be an essential immunomodulatory receptor, although P2X1 and P2X4 receptors also appear to be involved. ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses. The purinergic involvement in inflammation is being explored for the development of novel therapeutic strategies.

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Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

Cited by 198 publications

References 235 publications

Young capillary vessels rejuvenate aged pancreatic islets

Young capillary vessels rejuvenate aged pancreatic islets

Danger Signals From ATP and Adenosine in Pregnancy and Preeclampsia

P2X ion channel receptors and inflammation

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