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Updated: Apr 29, 2026
Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling
Desiree Anthony1, Jonathan L McQualter1, Maria Bishara1
1Department of Pharmacology and Therapeutics and.
Abstract:
Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11c(high)CD11b(high) macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11c(high)CD11b(high) macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11c(high)CD11b(high) macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.
Insights
Serum amyloid A (SAA) promotes a unique CD11c(high)CD11b(high) macrophage phenotype in chronic inflammation. Targeting these macrophages may offer new treatments for conditions like COPD.
Area of Science:
- Immunology
- Cell Biology
- Respiratory Medicine
Background:
- Serum amyloid A (SAA) is elevated in chronic inflammatory diseases like COPD.
- Macrophages accumulate in these conditions, exhibiting non-canonical M1/M2 phenotypes.
- The specific role of SAA in macrophage differentiation remains unclear.
Purpose of the Study:
- To investigate the role of SAA in regulating macrophage differentiation.
- To explore the impact of SAA on macrophage phenotype and function in vitro and in vivo.
- To identify potential therapeutic targets for SAA-mediated inflammation.
Main Methods:
- In vitro differentiation of human monocytes with SAA.
- In vivo airway SAA challenge model in mice.
- Analysis of macrophage markers, cytokine production, and phagocytic activity.
- Pharmacological inhibition of ALX/FPR2 and CSF-1R signaling.
Main Results:
- SAA induced pro-inflammatory cytokines (IL-6, IL-1β) and M2 markers (CD163, IL-10) in human monocytes.
- SAA-primed macrophages showed enhanced IL-6 and IL-1β production upon LPS stimulation.
- In vivo, SAA generated a CD11c(high)CD11b(high) macrophage population with increased cytokine output.
- CSF-1R blockade significantly reduced CD11c(high)CD11b(high) macrophages and neutrophilic inflammation.
Conclusions:
- SAA promotes a distinct CD11c(high)CD11b(high) macrophage phenotype.
- This SAA-induced macrophage population contributes to chronic inflammation.
- Targeting CD11c(high)CD11b(high) macrophages presents a potential therapeutic strategy for SAA-associated inflammatory diseases.
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