p53 integrates host defense and cell fate during bacterial pneumonia

Abstract

Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53 / mice display genome-wide induction of NF-B response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53 / neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53 / mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.

M1 macrophage dependent-p53 regulates the intracellular survival of mycobacteria

“…Owing to these regulatory functions, we hypothesized that p53 is involved in the modulation of macrophage polarization. Recent evidences have revealed that the presence of p53 is important for infected cells to have a bactericidal effect in various infectious diseases, including influenza, pneumonia, chlamydia, listeriosis and Helicobacter pylori infections [22][23][24][25][26][27]. Mtb infection also increases p53 gene expression in a human monocytic cell line [28] and peripheral blood human monocytes [29].…”

Transcriptional regulation of neutrophil differentiation and function during inflammation

“…118 This could be a mechanism by which p53-deficient neutrophils demonstrated extended lifespans and enhanced capacity of phagocytosis in response to inflammatory stimulation. 119,120 Recent studies have also demonstrated the mutual regulation between p53 and NF-B in inflammatory immune cells. 121,122 p53 inhibits NF-B transcriptional activity and attenuates the NF-B-dependent cytokine production by neutrophils by negatively regulating the NF-B activity downstream of IKK activation and I B-degradation.…”

“…In response to cellular stress, p53 promotes the expression of anti‐apoptotic protein Mcl‐1 . This could be a mechanism by which p53 ‐deficient neutrophils demonstrated extended lifespans and enhanced capacity of phagocytosis in response to inflammatory stimulation . Recent studies have also demonstrated the mutual regulation between p53 and NF‐κB in inflammatory immune cells .…”

A Non-invasive and Technically Non-intensive Method for Induction and Phenotyping of Experimental Bacterial Pneumonia in Mice

“…Finally, a critical and clinically highly relevant point that is revealed by in vivo pneumonia models is that successful pathogen clearance is not tantamount to success of the host. In many cases, an overexuberant immune response may lead to death of the host due to excessive bystander lung injury, even in the face of successful pathogen clearance 8,14 . Given this, parallel measurements of pathogen clearance and of the immune response are generally most informative, and survival studies may ultimately be required to reveal the integrated resilience of the host.…”