Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model

Leisman, Daniel E.; Privratsky, Jamie R.; Lehman, Jake R.; Abraham, Mabel; Yaipan, Omar Y.; Brewer, Mariana R.; Nedeljkovic-Kurepa, Ana; Capone, Christine; Fernandes, Tiago; Griffiths, Robert; Stein, William J.; Goldberg, Marcia B.; Crowley, Steven D.; Bellomo, Rinaldo; Deutschman, Clifford S.; Taylor, Matthew D.

doi:10.1073/pnas.2211370119

Cited by 17 publications

(9 citation statements)

References 51 publications

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“…This recruitment may allow an earlier and more efficient defense against pathogens (27,28). This effect may be like the one observed with angiotensin-II through the angiotensin-II type 1 receptor pathway (29). As exercise has an influence on the expression of angiotensin-II and angiotensin-II type 1 e149 receptor (30) this may explain the effect observed in our study.…”

Section: Discussionsupporting

confidence: 76%

Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia*

Vermeersch,

Léon,

Caillard

et al. 2024

Critical Care Medicine

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Objectives: An association between physical inactivity and worse outcome during infectious disease has been reported. The effect of moderate exercise preconditioning on the immune response during an acute pneumonia in a murine model was evaluated. Setting: Laboratory experiments. Subjects: C57BL6/j male mice. Interventions: Six-week-old C57BL/6J mice were divided in two groups: an exercise group and a control group. In the exercise group, a moderate, progressive, and standardized physical exercise was applied for 8 weeks. It consisted in a daily treadmill training lasting 60 minutes and with an intensity of 65% of the maximal theoretical oxygen uptake. Usual housing recommendation were applied in the control group during the same period. After 8 weeks, pneumonia was induced in both groups by intratracheal instillation of a fixed concentration of a Klebsiella pneumoniae (5 × 103 colony-forming unit) solution. Measurements and Main Results: Mice preconditioned by physical exercise had a less sever onset of pneumonia as shown by a significant decrease of the Mouse Clinical Assessment Severity Score and had a significantly lower mortality compared with the control group (27% vs. 83%; p = 0.019). In the exercise group, we observed a significantly earlier but transient recruitment of inflammatory immune cells with a significant increase of neutrophils, CD4+ cells and interstitial macrophages counts compared with control group. Lung tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 were significantly decreased at 48 hours after pneumonia induction in the exercise group compared with the control group. Conclusions: In our model, preconditioning by moderate physical exercise improves outcome by reducing the severity of acute pneumonia with an increased but transient activation of the innate immune response.

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Section: Discussionsupporting

confidence: 76%

Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia*

Vermeersch,

Léon,

Caillard

et al. 2024

Critical Care Medicine

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“…Another recent paper in a sepsis mouse model corroborated these findings, demonstrating that Ang II treatment ameliorates post‐CLP bacteremia in myeloid‐specific AT1A+ mice in comparison to Myeloid‐AT1A− mice. The results also show that the myeloid lineage‐mediated bacterial clearance is due to efficient monocyte phagocytosis and ROS induction following LPS treatment 158 …”

Section: Introductionmentioning

confidence: 64%

“…The results also show that the myeloid lineage-mediated bacterial clearance is due to efficient monocyte phagocytosis and ROS induction following LPS treatment. 158 Besides bacterial infection, the role of RAS components in cancer progression and response to treatment have been under active investigation by various research groups. 159 A significant number of patients with cancer diagnosis have increased levels of Ang II in blood and hypertension has been proposed as a major comorbid in cancer patients.…”

Section: Ras In Inflammation and Immune Responsementioning

confidence: 99%

Diverse biological functions of the renin‐angiotensin system

Rao,

Bhat,

Shibata

et al. 2023

Medicinal Research Reviews

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The renin‐angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS‐inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

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“…Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis ( 28 , 29 ). Therefore, we examined the effects of BMP9 treatment on bacterial burdens.…”

Section: Resultsmentioning

confidence: 99%

Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis

Bai,

Lu,

et al. 2024

Sci. Transl. Med.

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Defining next-generation immune therapeutics for the treatment of sepsis will involve biomarker-based therapeutic decision-making. Bone morphogenetic protein 9 (BMP9) is a cytokine in the transforming growth factor–β superfamily. Here, circulating BMP9 concentrations were quantified in two independent cohorts of patients with sepsis. Decreased concentrations of serum BMP9 were observed in the patients with sepsis at the time of admission as compared with healthy controls. Concentrations of BMP9 at the time of admission were also associated with 28-day mortality, because patients with sepsis at a higher risk of death had lower BMP9 concentrations. The mechanism driving the contribution of BMP9 to host immunity was further investigated using in vivo murine sepsis models and in vitro cell models. We found that BMP9 treatment improved outcome in mice with experimental sepsis. BMP9-treated mice exhibited increased macrophage influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. In vitro, BMP9 promoted macrophage recruitment, phagocytosis, and subsequent bacterial killing. We further found that deletion of the type 1 BMP receptor ALK1 in macrophages abolished BMP9-mediated protection against polymicrobial sepsis in vivo. Further experiments indicated that the regulation of macrophage activation by the BMP9-ALK1 axis was mainly mediated through the suppressor of mother against decapentaplegic 1/5 signaling pathway. Together, these results suggest that BMP9 can both serve as a biomarker for patient stratification with an independent prognostic value and be developed as a host-directed therapy for sepsis.

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Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model

Cited by 17 publications

References 51 publications

Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia*

Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia*

Diverse biological functions of the renin‐angiotensin system

Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis

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