Sensitization of the UPR by Loss of PPP1R15A Promotes Fibrosis and Senescence in IPF

Monkley, Susan J.; Overed-Sayer, Catherine; Parfrey, Helen; Rassl, Doris M.; Crowther, Damian C.; Escudero‐Ibarz, Leire; Davis, Niki; Carruthers, Alan; Berks, Richard; Coetzee, Marisa; Kolosionek, Ewa; Karlsson, Maria; Clausen, Maryam; Belfield, Graham; Hogaboam, Cory M.; Murray, Lynne

doi:10.21203/rs.3.rs-480385/v1

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…A previous study examining wound healing, showed that mice lacking PPP1R15a exhibited accelerated wound closure, increased number of myofibroblasts, and elevated collagen production 36 . A recent report has also shown that mice lacking Ppp1r15a show increased pulmonary fibrosis in response to the DNA damage inducing chemical bleomycin 37 . Taken together, these data suggest that the PP1R15A may play an important role in the negative regulation of fibrosis pathways.…”

Section: Discussionmentioning

confidence: 93%

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

Takaoka

Tadross

Al-Hadithi

et al. 2022

Preprint

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Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

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Section: Discussionmentioning

confidence: 93%

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

Takaoka

Tadross

Al-Hadithi

et al. 2022

Preprint

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“…CCL4 and CCL5 are potent chemo attractants for a variety of cells, among which are NK and T cells (25,26). IKBKB is an activator of NF-κB-dependent apoptotic pathways and PPP1R15A, whose functions associate with negative regulation of TGF-b signaling (27,28).…”

Section: Ifn-γ Mediates Adaptive Resistance In Bcg-unresponsive Tumorsmentioning

confidence: 99%

Elevated HLA-E and NKG2A as a Consequence of Chronic Immune Activation Defines Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

Ranti

Wang

Daza

et al. 2022

Preprint

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Mycobacterium bovis Bacillus Calmette-Guerin (BCG), the first line treatment for non-muscle invasive bladder cancer (NMIBC), promotes production of type I interferons, particularly interferon (IFN)-γ. Prolonged inflammation and IFN-γ exposure are known to cause an adaptive immune response, enabling immune escape and proliferation by tumor cells. We investigated HLA-E and NKG2A, a novel T and NK cell checkpoint pathway, as a driver of adaptive resistance in BCG unresponsive NMIBC. We observed ubiquitous inflammation in all patients after BCG immunotherapy, regardless of recurrence status. IFN-γ was shown to drive tumor expression of HLA-E and PD-L1. Further, NKG2A-expressing NK and CD8 T cells were enriched in BCG unresponsive tumors and with enhanced capacity for cytolytic functions. Strikingly, in situ spatial analyses revealed that HLA-EBRIGHT tumors are activated to recruit NK and T cells via chemokine production potentially sparing HLA-EDIM/NEG tumors that would otherwise be susceptible to lysis. Finally, blood-derived NK cells retained antitumor functions at time of tumor recurrence. These data support combined NKG2A and PD-L1 blockade for BCG unresponsive disease.

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Sensitization of the UPR by Loss of PPP1R15A Promotes Fibrosis and Senescence in IPF

Cited by 2 publications

References 30 publications

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

Elevated HLA-E and NKG2A as a Consequence of Chronic Immune Activation Defines Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

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