Cardiolipin-mediated PPARγ S112 phosphorylation impairs IL-10 production and inflammation resolution during bacterial pneumonia

Garg, Mayank; Johri, Saumya; Sagar, Shakti; Mundhada, Aniruddha; Agrawal, Anurag; Ray, Prabir; Chakraborty, Krishnendu

doi:10.1016/j.celrep.2021.108736

Cited by 20 publications

(18 citation statements)

References 82 publications

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“…Instead, loss of TG2 delayed the rise in the CD206 mannose receptor [41], Arg1, GDF3, and IL-10-producing cells. Interestingly, the expression of all these factors is known to be regulated by PPARγ [7,42,43], a transcription factor playing a central role in the phenotypic switch of macrophages. Accordingly, we detected significantly lower PPARγ mRNA levels in the CD45 + cells derived from theTG2 null regenerating TA muscles.…”

Section: Discussionmentioning

confidence: 99%

Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Budai

Al‐Zaeed

Szentesi

et al. 2021

Cells

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Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammatory cytokines induce satellite cell proliferation and differentiation into myoblasts, growth factors, such as GDF3, released by healing macrophages drive myoblast fusion and myotube growth. Therefore, improper efferocytosis may lead to impaired muscle regeneration. Transglutaminase 2 (TG2) is a versatile enzyme participating in efferocytosis. Here, we show that TG2 ablation did not alter the skeletal muscle weights or sizes but led to the generation of small size myofibers and to decreased grip force in TG2 null mice. Following cardiotoxin-induced injury, the size of regenerating fibers was smaller, and the myoblast fusion was delayed in the tibialis anterior muscle of TG2 null mice. Loss of TG2 did not affect the efferocytic capacity of muscle macrophages but delayed their conversion to Ly6C−CD206+, GDF3 expressing cells. Finally, TG2 promoted myoblast fusion in differentiating C2C12 myoblasts. These results indicate that TG2 expressed by both macrophages and myoblasts contributes to proper myoblast fusion, and its ablation leads to impaired muscle development and regeneration in mice.

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Section: Discussionmentioning

confidence: 99%

Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Budai

Al‐Zaeed

Szentesi

et al. 2021

Cells

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“…To investigate the role of Selenbp1 in cardiac fibrosis, we performed in vivo gene silencing using Selenbp1 siRNA (AM16830, Invitrogen) along with a transfection reagent, as previously described 25 but with some modification. Forty micrograms of siRNA combined with the non‐viral in vivo transfection reagent JetPEI® (Polyplus‐transfection) was administered three times every week to each rat through tail‐vein injection.…”

Section: Methodsmentioning

confidence: 99%

Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover

2023

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Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel-coated dishes supplemented with recombinant TGFβ protein, respectively. Matrix-degrading myocardium was cultured in 64 kPa silicone gel-coated dishes with recombinant TGFβ protein and then in 16 kPa silicone gel-coated dishes. Cardiac fibroblasts were cultured in this three-part in vitro pathological models and compared.Fibroblasts differentiated into activated or matrix-degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix-degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis.

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“…It was reported that genetic inhibition of PPARγ S112 increased adipogenesis (Ge et al, 2018;van Beekum et al, 2009), indicating an anti-adipogenic effect of PPARγ S112. Literature was also reported that PPARγ S112 phosphorylation impairs anti-inflammatory mechanism in bacterial pneumonia (Garg et al, 2021), which suggested its proinflammatory effect. However, we did not observe changes of PPARγ phosphorylation at S112 in the obese diabetic mouse brain where inflammation was presented.…”

Section: Discussionmentioning

confidence: 96%

Pioglitazone attenuates ischaemic stroke aggravation by blocking PPARγ reduction and inhibiting chronic inflammation in diabetic mice

Guo

Zuo

Yin

et al. 2022

Eur J of Neuroscience

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Diabetes can cause vascular remodelling and is associated with worse outcome after ischaemic stroke. Pioglitazone is a commonly used anti-diabetic agent. However, it is not known whether pioglitazone use before ischaemia could reduce brain ischaemic injury. Pioglitazone was administered to 5-week-old db + or db/db mice. Cerebral vascular remodelling was examined at the age of 9 weeks.Expression of peroxisome proliferator-activated receptor-γ (PPARγ), p-PPARγ (S112 and S273), nucleotide-binding domain (NOD)-like receptor protein 3 (Nlrp3), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) was evaluated in the somatosensory cortex of mice. Neurological outcome was evaluated 24 h after brain ischaemia. Results showed that early pioglitazone treatment provided a long-lasting effect of euglycaemia but enhanced hyperlipidaemia in the db/db mice. Diabetic mice exhibited increased vascular tortuosity, narrower middle cerebral artery (MCA) width and IgG leakage in the brain. These changes were blocked by early pioglitazone treatment. In diabetic animals, PPARγ expression was reduced, and p-PPARγ at S273 but not S112, Nlrp3, IL-1β and TNF-α were increased in the somatosensory cortex. PPARγ decrease and Nlrp3 increase were mainly in the neurons of the diabetic brain, which was reversed by early pioglitazone treatment. Pioglitazone attenuated the aggravated neurological outcome after stroke in diabetic mice.

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Cardiolipin-mediated PPARγ S112 phosphorylation impairs IL-10 production and inflammation resolution during bacterial pneumonia

Cited by 20 publications

References 82 publications

Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover

Pioglitazone attenuates ischaemic stroke aggravation by blocking PPARγ reduction and inhibiting chronic inflammation in diabetic mice

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