Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153

Abstract

PurposeProgrammed Death-1 (PD-1) and its ligand, PD-L1, are regulators of immune/ inflammatory mechanisms. We explored the potential involvement of PD-1/PD-L1 pathway in the inflammatory response and tissue damage in cardiac injury models.Experimental DesignIschemic-reperfused and cryoinjured hearts were processed for flow cytometry and immunohistochemical studies for determination of cardiac PD-1 and PD-L1 in the context of assessment of the growth arrest- and DNA damage-inducible protein 153 (GADD153) which regulates both inflammation and cell death. Further, we explored the potential ability of injured cardiac cells to influence proliferation of T lymphocytes.ResultsThe isolated ischemic-reperfused hearts displayed marked increases in expression of PD-1 and PD-L1 in cardiomyocytes; however, immunofluorescent studies indicate that PD-1 and PD-L1 are not primarily co-expressed on the same cardiomyocytes. Upregulation of PD-1/PD-L1 was associated with a) marked increases in GADD153 and interleukin (IL)-17 but a mild increase in IL-10 and b) disruption of mitochondrial membrane potential (ψm) as well as apoptotic and necrotic cell death. Importantly, while isotype matching treatment did not affect the aforementioned changes, treatment with the PD-L1 blocking antibody reversed those effects in association with marked cardioprotection. Further, ischemic-reperfused cardiac cells reduced proliferation of T lymphocytes, an effect partially reversed by PD-L1 antibody. Subsequent studies using the cryoinjury model of myocardial infarction revealed significant increases in PD-1, PD-L1, GADD153 and IL-17 positive cells in association with significant apoptosis/necrosis.ConclusionsThe data suggest that upregulation of PD-1/PD-L1 pathway in cardiac injury models mediates tissue damage likely through a paracrine mechanism. Importantly, inhibition of T cell proliferation by ischemic-reperfused cardiac cells is consistent with the negative immunoregulatory role of PD-1/PD-L1 pathway, likely reflecting an endogenous cardiac mechanism to curtail the deleterious impact of infiltrating immune cells to the damaged myocardium. The balance of these countervailing effects determines the extent of cardiac injury.

Cardiotoxicity danger in immunotherapy

“…Acute coronary syndrome in BALB/c mice increased the percentage of heart cells expressing PD‐1+ and PD‐L1+. These experiments confirmed that PD‐1/PD‐L1 play an important role in reducing T‐cell‐mediated autoimmune myocarditis 35 …”

“…The expression of GADD153 in proliferating cells is very low, but it is strongly induced by cellular stresses, such as glucose deprivation, genotoxic agents, and other growth‐arresting factors. Knockdown of GADD153 confers cardioprotective effect in mice model 35 . PD‐1/PD‐L1 pathway activation leads to inhibition of the prosurvival signaling in T cells like PI3K/Akt pathway, which is an important kinase pathway after reperfusion injury.…”

Fibrinogen‐like protein‐2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death‐1 and inflammatory cytokines

“…Fibrinogen‐like protein 2 (FGL2), a member of the fibrinogen family, is expressed either as a pro‐coagulative membrane protein or as an immunosuppressive secreted protein . FGL2 over‐expression resulted in deterioration of heart function in rats with acute EAM, increased the inflammatory cell infiltrations, and increased the level of brain natriuretic peptide (BNP), tumour necrosis factor‐ α , interleukin‐6 (IL‐6) and IL‐17 Increased expression of PD‐1/PD‐L1 in ischaemia re‐perfused and cryoinjured hearts was associated with a marked increase in IL‐17 . In our current study we explored the involvement of the PD‐1/PD‐L1 pathway in immunotolerance as a potential mechanism for the pathogenesis of EAM mediated by FGL2.…”

Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes

“…These mice experience increased influx of monocytes, CD4 T cells, and CD8 T cells in association with increased TNFα. However, the role of PD-1 ligation in human atherosclerosis remains uncertain 383940 . It is against this background that we find phenotypically naive CD8 T cells from ACS patients have a reduced capacity for IL-2 production, and this correlates with increased expression of PD-1.…”