P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing. 1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This 'plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype. 2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years.P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair. 3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer, 4 the role of p53 in inflammation is not clear. Macrophages from p53 − / − mice produce increased quantities of proinflammatory cytokines in response to LPS, 5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53 − ...
AimsThe national lockdowns due to the COVID-19 pandemic, have had a considerable effect on mental health, with reduced access to social interaction through work and leisure activities, and increased barriers to community mental health services.This study aims to evaluate how the presentation of patients with self-injury has changed during the first national U.K. lockdown, at a Plastic Surgery Tertiary Referral Centre in the East of England.MethodRetrospectively recorded data from 23 March 2020 to 31 December 2020, spanning the duration of the first two lockdowns in the UK, were compared to the same period in 2019. The demographics of patients, along with the nature, severity and outcomes of the self-injury were recorded and compared.ResultThe number of patients referred for self-injury reduced by 22.9% during lockdown (2020: N = 42/109, 2019: 67/109)The most common attendance route was via ambulance during lockdown (2020:40.5% 2019: 31.3%) whilst the most common attendance route being via the front door in 2019 (2019: 35.8%, 2020: 26.2%)The number of new presentations with no prior history of self-injury was higher in lockdown 38.1%) compared to 2019 26.9%.The lockdown cohort had a smaller proportion of patients presenting with complications (2020: 9.5% vs 2019: 17.9%), less readmitted (2020: 11.9% vs 2019: 23.9%). Similar re-attendance rate (2020: 40.3% vs 2019: 38.1%) and re-intervention (2020: 13.4% vs 2019: 14.3%).A greater proportion in 2020 met the threshold for inpatient psychiatry input (2020: 52.4% vs 2019: 41.8%).During the lockdown, a higher percentage of flexor tendon injuries involved multiple tendons (60.0% vs 52.2%). A higher percentage of extensor tendon injuries (14.3% vs 7.4%), and a greater proportion of these also involved multiple tendons (66.7% vs 40.0%). More self-injuries were complicated by fractures (7.1% vs 4.5%) and more required soft tissue reconstruction (11.9% vs 3.0%).ConclusionDespite fewer patients presenting with self-injury during the 2020 lockdown, the injuries were more severe. Many of which had multiple structural injuries, and some with life-changing injuries, this is in line with our clinical observations.During lockdown there was a higher proportion of first-time presentations without a history of self-injury and an increased need for inpatient psychiatry input. This may reflect the impact on mental health as a result of restricted social interactions.These findings demonstrate the impact of lockdown on mental-health and may help inform medical services of potential changes in the presentations in future national social restrictions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.