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p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β
Gorjana Rackov, … , Carlos Martínez-A, Dimitrios Balomenos
Gorjana Rackov, … , Carlos Martínez-A, Dimitrios Balomenos
Published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):3089-3103. https://doi.org/10.1172/JCI83404.
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Research Article Immunology

p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β

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Abstract

M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 macrophage reprogramming that develops during LPS tolerance resembles the pathological antiinflammatory response to sepsis. Here, we determined that p21 regulates macrophage reprogramming by shifting the balance between active p65-p50 and inhibitory p50-p50 NF-κB pathways. p21 deficiency reduced the DNA-binding affinity of the p50-p50 homodimer in LPS-primed and -rechallenged macrophages, impairing their ability to attenuate IFN-β production and acquire an M2-like hyporesponsive status. High p21 levels in sepsis patients correlated with low IFN-β expression, and p21 knockdown in human monocytes corroborated its role in IFN-β regulation. The data demonstrate that p21 adjusts the equilibrium between p65-p50 and p50-p50 NF-κB pathways to mediate macrophage plasticity in LPS tolerance. Identifying p21-related pathways involved in monocyte reprogramming may lead to potential targets for sepsis treatment.

Authors

Gorjana Rackov, Enrique Hernández-Jiménez, Rahman Shokri, Lorena Carmona-Rodríguez, Santos Mañes, Melchor Álvarez-Mon, Eduardo López-Collazo, Carlos Martínez-A, Dimitrios Balomenos

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Figure 1

p21 controls in vivo endotoxin tolerance.

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p21 controls in vivo endotoxin tolerance.
(A) P21–/– and WT mice (n = 6)...
(A) P21–/– and WT mice (n = 6) were treated with a single, high LPS dose, and showed 100% death (left). To induce tolerance, P21–/– and WT mice (n = 10) received a low LPS dose, followed by a high dose after 16 hours. P21–/– mice did not develop tolerance compared to WT mice, as indicated by a Kaplan-Meier survival curve (right). **P < 0.01, log‑rank (Mantel-Cox) test. (B) Blood was collected 2 hours after the second LPS injection and serum cytokines measured by ELISA. Levels of M1-associated cytokines (TNF-α and IFN-β) were elevated in the serum of P21–/– compared with WT mice. Data show the mean ± SD (n = 3 mice), *P < 0.05, 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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