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Impairment of macrophage activation and granuloma formation by protein deprivation in mice
J V Reynolds1, H P Redmond, N Ueno
1Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia 19104.
Abstract:
Protein-calorie malnutrition predisposes to infection by intracellular pathogens, but the basis for this predisposition is unclear. We studied the effect of protein deprivation on mouse peritoneal macrophage function and on granuloma formation during infection by bacille Calmette-Gueŕin (BCG). Injection of lipopolysaccharide (LPS) to induce inflammation elicited fewer peritoneal cells from mice fed a 2.5% protein diet than from mice fed an isocaloric chow in which protein calories constituted 24% of the total. LPS-elicited macrophages from protein-deprived mice demonstrated a reduction in spreading, total cell protein, cell lactate dehydrogenase, and release of superoxide anion (O2-) in response to stimulation. Priming in vitro by interferon (IFN)-gamma for enhanced release of O2- was also significantly impaired in protein-deprived mice. This defect was reversible by repletion with 24% protein diet for 10 days. Impairment of macrophage function in protein-deprived mice was further evidenced by an impaired capacity to express Ia antigen in response to IFN-gamma and by reduced production of IL-1 activity in response to LPS. Infection by BCG in protein-deprived mice was characterized by impaired granuloma development in liver, lungs, and spleen. Thus, in this model, protein deprivation significantly impaired macrophage activation, as assessed by morphologic, metabolic, and functional criteria. This impairment might compromise immune effector mechanisms dependent on macrophage activation, including rejection of intracellular pathogens.
Insights
Protein deficiency impairs macrophage function, hindering the immune system's ability to fight intracellular pathogens like bacille Calmette-Gueŕin (BCG). This study reveals compromised immune responses in malnourished mice.
Area of Science:
- Immunology
- Nutrition Science
- Pathology
Background:
- Protein-calorie malnutrition is linked to increased susceptibility to intracellular infections.
- The precise mechanisms underlying this increased susceptibility, particularly concerning macrophage function, remain incompletely understood.
Purpose of the Study:
- To investigate the impact of protein deprivation on mouse peritoneal macrophage function.
- To examine the effect of protein deficiency on granuloma formation during infection with bacille Calmette-Gueŕin (BCG).
Main Methods:
- Mice were fed either a low-protein (2.5%) or a normal-protein (24%) diet.
- Lipopolysaccharide (LPS) was used to elicit peritoneal macrophages, and their function was assessed.
- Interferon-gamma (IFN-γ) was used for in vitro priming to evaluate enhanced superoxide anion (O2-) release.
- Macrophage Ia antigen expression and Interleukin-1 (IL-1) production were measured.
- Granuloma formation was assessed in liver, lungs, and spleen following BCG infection.
Main Results:
- Protein-deprived mice exhibited reduced numbers of elicited peritoneal cells.
- Macrophages from protein-deficient mice showed impaired spreading, reduced total protein and lactate dehydrogenase, and diminished O2- release upon stimulation.
- The ability of macrophages to enhance O2- release after IFN-γ priming was significantly impaired.
- Defects in macrophage function, including reduced Ia antigen expression and IL-1 production, were observed.
- BCG infection in protein-deprived mice resulted in impaired granuloma development in multiple organs.
Conclusions:
- Protein deprivation significantly impairs macrophage activation, affecting morphologic, metabolic, and functional parameters.
- This compromised macrophage activation may weaken immune defenses against intracellular pathogens.
- The observed defects in macrophage function were reversible upon dietary repletion.