The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model

Hayashi, Tomohiro; Tiwary, Sajal K.; Lavine, Kory J.; Acharya, Sandeep; Brent, Michael R.; Adamo, Luigi; Kovács, Attila; Mann, Douglas L.

doi:10.1016/j.jacbts.2022.05.006

Cited by 21 publications

(29 citation statements)

References 54 publications

(69 reference statements)

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“…This statement notwithstanding, we have shown previously that high mobility group box 1 (HMGB1), a non-histone nuclear protein that is known to skew monocyte derived macrophages towards an classically activate phenotype, are enriched in NCEs. Fourth, although we did not identify which receptors were responsible for NCE-induced macrophage skewing in the present study, we have shown recently that necrotic myocardial extracts activate macrophages through both TLR4 and TLR2 [ 22 , 23 ]. Lastly, although the present study was focused on the role of necrosis on macrophage polarization, it should be recognized that efferocytosis of apoptotic cells by macrophages can lead to skewing towards an anti-inflammatory (i.e.…”

Section: Discussionmentioning

confidence: 65%

Necrotic cardiac myocytes skew macrophage polarization towards a classically activated phenotype

et al. 2023

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Necrotic and dying cells release damage-associated molecular patterns (DAMPs) that can initiate sterile inflammatory responses in the heart. Although macrophages are essential for myocardial repair and regeneration, the effect of DAMPs on macrophage activation remains unclear. To address this gap in knowledge we studied the effect of necrotic cardiac myocyte extracts on primary peritoneal macrophage (PPM) cultures in vitro. We first performed unbiased transcriptomic profiling with RNA-sequencing of PPMs cultured for up to 72 hours in the presence and absence of: 1) necrotic cell extracts (NCEs) from necrotic cardiac myocytes in order to mimic the release of DAMPs; 2) lipopolysaccharide (LPS), which is known to polarize macrophages towards a classically activated phenotype and 3) Interleukin-4 (IL-4), which is known to promote polarization of macrophages towards an alternatively activated phenotype. NCEs provoke changes in differential gene expression (DEGs) that had considerable overlap with LPS-induced changes, suggesting that NCEs promote macrophage polarization towards a classically activated phenotype. Treating NCEs with proteinase-K abolished the effects of NCEs on macrophage activation, whereas NCE treatment with DNase and RNase did not affect macrophage activation. Stimulation of macrophage cultures with NCEs and LPS resulted in a significant increase in macrophage phagocytosis and interleukin-1β secretion, whereas treatment with IL-4 had no significant effect on phagocytosis and interleukin-1β. Taken together, our findings suggest that proteins released from necrotic cardiac myocytes are sufficient to skew the polarization of macrophages towards a classically activated phenotype.

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Section: Discussionmentioning

confidence: 65%

Necrotic cardiac myocytes skew macrophage polarization towards a classically activated phenotype

et al. 2023

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“…Recent work has identified the temporal course of a chronic inflammatory response in stress cardiomyopathy, with an initial early influx of neutrophils into myocardial tissue followed by proinflammatory macrophages and increase in systemic inflammatory cytokines with activation of downstream signaling pathways. 8 In this issue of JACC: Basic to Translational Science , Hayashi et al 9 leveraged a similar approach by simulating cardiac injury using high-dose isoproterenol, a sympathomimetic stimulus previously shown to result in hemodynamic and ischemic stress. By simulating stress cardiomyopathy, these investigators introduced a process that is classically thought to be unrelated with the inflammatory milieu.…”

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confidence: 99%

“…Mice treated with PD-L1 inhibitor prior to isoproterenol had a higher mortality rate, as well as higher troponin elevation on isoproterenol injection, whereas PD-1–deficient mice were slower to recover from wall motion abnormalities and without full recovery to baseline at 7 days. 9 Indeed, this degree of additional cardiomyopathy was not shown with administration of programmed cell death protein (PD)-2 inhibitors in wild-type mice. 9 Taken together, these findings imply that the PD-1/PD-L1 pathway not only plays a role in suppressing autoreactive T-cell–mediated immune disease, but the pathway also engages the innate immune system in the autoregulation of the inflammatory response after tissue injury.…”

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confidence: 99%

“… 9 Indeed, this degree of additional cardiomyopathy was not shown with administration of programmed cell death protein (PD)-2 inhibitors in wild-type mice. 9 Taken together, these findings imply that the PD-1/PD-L1 pathway not only plays a role in suppressing autoreactive T-cell–mediated immune disease, but the pathway also engages the innate immune system in the autoregulation of the inflammatory response after tissue injury. It appears that inhibition of the pathway allows for prolonged and/or excessive inflammation and subsequent myocardial injury, resulting in the manifestations that would be judged clinically as stress cardiomyopathy or myocarditis.…”

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confidence: 99%

“…Though employing previously established protocols, Hayashi et al 9 introduce several novel insights that may have implications in understand the protocols’ roles promoting myocardial recovery. First, it is pertinent to consider the intersection between ICI-induced cardiotoxicity and other forms of immune-mediated cardiomyopathies with stress cardiomyopathy in a broader spectrum.…”

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Keeping the Failing Heart in Check

Zheng

Tang

2022

JACC: Basic to Translational Science

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Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice

Rubio‐Infante,

Castillo,

Alves‐Figueiredo

et al. 2023

ESC Heart Failure

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AimsImmune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune‐related adverse events, particularly when combined (e.g., anti‐CTLA‐4 plus anti‐PD‐1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy‐induced myocarditis.MethodsWe evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure‐volume (PV)‐loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies).ResultsAfter the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF‐α (<0.0001) increased 2.5‐ and 1.7‐fold, respectively, in the treated group, while IL‐6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature.ConclusionsOur findings indicate that pre‐existing sustained cardiac damage is a necessary condition for ICI‐induced myocarditis.

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The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model

Cited by 21 publications

References 54 publications

Necrotic cardiac myocytes skew macrophage polarization towards a classically activated phenotype

Necrotic cardiac myocytes skew macrophage polarization towards a classically activated phenotype

Keeping the Failing Heart in Check

Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor‐associated lethal myocarditis in mice

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