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Murine leukocyte dysfunction in response to a non-lethal flame burn
Adrienne R Kambouris1, Jerod A Brammer2, Gideon Wolf3
1Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract:
In a non-lethal, 10% total body surface area, full-thickness flame mouse model, infections with Pseudomonas aeruginosa (PA) increased mortality post-burn, suggesting an impaired host immune response. The presence of a seroma beneath the burn wound sequesters CD45+ cells. Furthermore, in the case of burn and infection, PA was found to be in proximity to these cells but was not phagocytosed, suggesting leukocyte dysfunction. In this study, leukocytes isolated from the circulation and seroma of burned mice had a decreased ability to kill PA compared to the circulating leukocytes of Sham mice. Both Sham and burned mouse leukocytes lost the ability to kill when incubated in vitro with seroma fluid. Leukocytes from the seroma had a decreased ability to produce reactive oxygen species (ROS) following stimulation when compared to leukocytes isolated from the circulation of the same burned mice. Sham leukocytes incubated with sera from burned mice and burned and infected mice, but not with sera from Sham mice, significantly produce ROS at rest, which may be correlated with the pro-inflammatory danger-associated molecular pattern (DAMP) HMGB1 in the sera of burned mice. These data suggest that a non-lethal burn can prematurely activate leukocytes while in circulation, reducing their functionality at the infected burn site, and that leukocytes at the burn site (seroma) also have impaired function. We conclude that an otherwise non-lethal burn prematurely activates circulating leukocytes and that the seroma environment further inhibits the leukocytes that arrive at the burn site. This results in an impaired immune response and the development of lethal sepsis.
Insights
A non-lethal burn impairs immune cells, leading to increased mortality in Pseudomonas aeruginosa infections. Leukocytes become dysfunctional in circulation and at the burn site, causing lethal sepsis.
Area of Science:
- Immunology
- Wound Healing
- Microbiology
Background:
- Burn injuries can compromise host immunity, increasing susceptibility to infections like Pseudomonas aeruginosa (PA).
- Seroma formation under burn wounds sequesters immune cells, potentially affecting their function.
- Leukocyte dysfunction is implicated in impaired host defense following burns and infection.
Purpose of the Study:
- To investigate the functional status of leukocytes in a mouse model of burn injury and PA infection.
- To determine the impact of seroma fluid on leukocyte antimicrobial activity.
- To explore the role of serum components and danger-associated molecular patterns (DAMPs) in leukocyte activation and dysfunction.
Main Methods:
- Utilized a non-lethal, 10% total body surface area flame burn mouse model with PA infection.
- Isolated leukocytes from circulation and seroma fluid for functional assays (PA killing, reactive oxygen species production).
- Incubated leukocytes with seroma fluid and serum from burned/infected mice to assess in vitro effects.
Main Results:
- Leukocytes from burned mice exhibited reduced ability to kill PA compared to controls.
- Seroma fluid incubation impaired the killing capacity of both Sham and burned mouse leukocytes.
- Leukocytes from seroma showed decreased reactive oxygen species (ROS) production compared to circulating leukocytes.
- Serum from burned mice induced resting ROS production in Sham leukocytes, potentially linked to HMGB1.
Conclusions:
- A non-lethal burn prematurely activates circulating leukocytes, compromising their function at the infection site.
- The burn wound microenvironment, specifically seroma fluid, further inhibits leukocyte function.
- Impaired leukocyte activity contributes to a weakened immune response, leading to increased mortality from sepsis post-burn and infection.
