Author: Tóth, Emese ; Mahdi, Mohamed ; Hirsch, Edit ; Jakab, Ferenc ; Méhes, Gábor ; Bai, Péter ; Madai, Mónika ; Bánfai, Krisztina ; Juhász, Péter ; Pongrácz, Judit E. ; Tőzsér, József ; Petri, László ; Papp, Henrietta ; Vaskó, Dorottya ; Helyes, Zsuzsanna ; Keserű, György M. ; Szalai, Tibor Viktor ; Bohus, Péter ; Russo, Lilian Cristina ; Bajusz, Dávid ; Curtin, Nicola J. ; Hoch, Nicolas C. ; Kemény, Ágnes ; Sipos, Adrienn ; Bóvári‐Biri, Judit ; Mózner, Orsolya ; Kuczmog, Anett ; Batta, Gyula ; Tóth, Attila

AbstractBackground and PurposeTo date, there are limited options for severe Coronavirus disease 2019 (COVID‐19), caused by SARS‐CoV‐2 virus. As ADP‐ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID‐19.Experimental ApproachThe effects of PARP inhibitors on virus uptake were assessed in cell‐based experiments using multiple variants of SARS‐CoV‐2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti‐inflammatory properties of rucaparib were demonstrated in cell‐based models upon challenging with recombinant spike protein or SARS‐CoV‐2 RNA vaccine.Key ResultsWe detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID‐19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS‐CoV‐2 infection rate through binding to the conserved 493–498 amino acid region located in the spike‐ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA‐induced overexpression of cytokines was down‐regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations.Conclusion and ImplicationsThese results point towards repurposing rucaparib for treating inflammatory responses in COVID‐19.

01 Aug 2024·Immunology & Cell Biology

Loss of Bcl‐3 regulates macrophage polarization by promoting macrophage glycolysis

Article

Author: Liang, Yinming ; Wang, Hao ; Wang, Hui ; Li, Jiaoyang ; Gao, Jingtao ; Cui, Mengchao ; Yu, Li ; Zhao, Yuxin ; Liu, Shengnan ; Wei, Xiaofei

AbstractM1/M2 macrophage polarization plays an important role in regulating the balance of the microenvironment within tissues. Moreover, macrophage polarization involves the reprogramming of metabolism, such as glucose and lipid metabolism. Transcriptional coactivator B‐cell lymphoma‐3 (Bcl‐3) is an atypical member of the IκB family that controls inflammatory factor levels in macrophages by regulating nuclear factor kappa B pathway activation. However, the relationship between Bcl‐3 and macrophage polarization and metabolism remains unclear. In this study, we show that the knockdown of Bcl‐3 in macrophages can regulate glycolysis‐related gene expression by promoting the activation of the nuclear factor kappa B pathway. Furthermore, the loss of Bcl‐3 was able to promote the interferon gamma/lipopolysaccharide‐induced M1 macrophage polarization by accelerating glycolysis. Taken together, these results suggest that Bcl‐3 may be a candidate gene for regulating M1 polarization in macrophages.

01 Jul 2024·Cell Reports

IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression

Article

Author: Neyens, Damien ; Deschamps, Mélanie ; Montiel, Virginie ; Wildmann, Claude ; Vanhaver, Christophe ; van der Bruggen, Pierre ; Squifflet, Jean-Luc ; Sala de Oyanguren, Francisco ; Dauguet, Nicolas ; Hirsch, Thibault ; Luyckx, Mathieu ; Bayard, Alexandre ; Duhamel, Céline

Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4⁺ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

100 Deals associated with IKK-16

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Discovery	United States	Duke University	-
Malaria	Discovery	United States	The University of North Carolina at Chapel Hill	-
Malaria	Discovery	United States	Luceome Biotechnologies, L L C	-

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