PPAR Regulation of Inflammatory Signaling in CNS Diseases

Bright, John J.; Kanakasabai, Saravanan; Chearwae, Wanida; Chakraborty, Sharmistha

doi:10.1155/2008/658520

Cited by 103 publications

(93 citation statements)

References 109 publications

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“…Although it is unknown whether genetic variants of PPARγ influence the expression of emphysema, a recent case-control study showed that a slow-activity variant of PPARγ was associated with increased COPD susceptibility in a homogeneous population (48). Similarly, reduced circulating PPARγ in smokers has been linked to the development of other autoimmune diseases such as MS (49,50), psoriasis (51), and RA (52). Type 2 diabetes mellitus is also increasingly being recognized as an inflammatory disorder of macrophages (53).…”

Section: Figurementioning

confidence: 99%

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

Shan¹,

You²,

Yuan³

et al. 2014

J. Clin. Invest.

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The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg flox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg flox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

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Section: Figurementioning

confidence: 99%

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

Shan¹,

You²,

Yuan³

et al. 2014

J. Clin. Invest.

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“…There are three isoforms currently identified including PPAR ␣ , PPAR ␤ / ␦ and PPAR ␥ , each with splice variants. Natural ligands include eicosanoids and prostaglandin J 2 , in addition to the synthetic thiazolidinedones, pioglitazone and rosiglitazone [26] . PPARs are involved in several processes including lipid and glucose metabolism, adipocyte differentiation and cholesterol homeostasis.…”

Section: Peroxisome Proliferator-activated Receptorsmentioning

confidence: 99%

Inflammation and Anti-Inflammatory Strategies for Alzheimer’s Disease – A Mini-Review

et al. 2009

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Until recently, the central nervous system (CNS) has been thought to be an immune privileged organ. However, it is now understood that neuroinflammation is linked with the development of several CNS diseases including late-onset Alzheimer’s disease (LOAD). The development of inflammation is a complex process involving a wide array of molecular interactions which in the CNS remains to be further characterized. The development of neuroinflammation may represent an important link between the early stages of LOAD and its pathological outcome. It is proposed that risks for LOAD, which include genetic, biological and environmental factors can each contribute to impairment of normal CNS regulation and function. The links between risk factors and the development of neuroinflammation are numerous and involve many complex interactions which contribute to vascular compromise, oxidative stress and ultimately neuroinflammation. Once this cascade of events is initiated, the process of neuroinflammation can become overactivated resulting in further cellular damage and loss of neuronal function. Additionally, neuroinflammation has been associated with the formation of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of LOAD. Increased levels of inflammatory markers have been correlated with an advanced cognitive impairment. Based on this knowledge, new therapies aimed at limiting onset of neuroinflammation could arrest or even reverse the development of the disease.

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“…Indeed, their involvement in neurodegenerative Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, Parkinson, and Huntington diseases, is well recognized. [15][16][17][18][19][20][21][22] Even though PPAR β/δ is the most abundant isotype in the developing and adult central nervous system (CNS), [23][24][25] its role in neurodegenerative diseases remains unclear. We have previously demonstrated that PPAR β/δ is crucial for neuronal maturation, and that its expression affects the BDNF signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: Possible role of 4-hydroxynonenal (4-HNE)

et al. 2014

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Aging and many neurological disorders, such as AD, are linked to oxidative stress, which is considered the common effector of the cascade of degenerative events. In this phenomenon, reactive oxygen species play a fundamental role in the oxidative decomposition of polyunsaturated fatty acids, resulting in the formation of a complex mixture of aldehydic end products, such as malondialdehyde, 4-hydroxynonenal, and other alkenals. Interestingly, 4-HNE has been indicated as an intracellular agonist of peroxisome proliferator-activated receptor β/δ. In this study, we examined, at early and advanced AD stages (3, 9, and 18 months), the pattern of 4-HNE and its catabolic enzyme glutathione S-transferase P1 in relation to the expression of PPAR β/δ, BDNF signaling, as mRNA and protein, as well as on their pathological forms (i.e., precursors or truncated forms). The data obtained indicate a novel detrimental age-dependent role of PPAR β/δ in AD by increasing pro-BDNF and decreasing BDNF/TrkB survival pathways, thus pointing toward the possibility that a specific PPARβ/δ antagonist may be used to counteract the disease progression. © 2014 Landes Bioscience

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PPAR Regulation of Inflammatory Signaling in CNS Diseases

Cited by 103 publications

References 109 publications

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

Inflammation and Anti-Inflammatory Strategies for Alzheimer’s Disease – A Mini-Review

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: Possible role of 4-hydroxynonenal (4-HNE)

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