Introduction
The acute-phase response (APR) is a critical physiological reaction to various forms of stress, including infection, trauma, and severe disease. This systemic response is characterized by rapid changes in plasma protein levels, among which serum amyloid A (SAA) is one of the most notable. SAA levels can increase by up to 1000-fold during APR, making it a prominent marker for acute inflammation.
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SAA's significant elevation in various inflammatory conditions such as rheumatoid arthritis, atherosclerosis, Crohn's disease, and type 2 diabetes underscores its potential role in these diseases. Historically considered a passive marker of inflammation, recent research suggests that SAA may have more active involvement in the inflammatory process. This article reviews current knowledge on SAA's role in inflammation, its interactions with receptors, and its signaling mechanisms, while highlighting unresolved issues and future research needs.
Fig. 1 Organization of the four members of the human Saa gene family on chromosome 11p (Sack Jr G. H. 2018).
SAA Genes and Subtypes
SAA comprises a family of small proteins with 104 amino acids in their mature forms. In humans, SAA is encoded by four closely related genes on chromosome 11: SAA1, SAA2, SAA3, and SAA4. SAA1 and SAA2 are inducible acute-phase proteins, whose expression is triggered by inflammatory signals such as IL-1β, IL-6, and lipopolysaccharides (LPS). These genes are regulated by transcription factors including NF-κB, AP-1, and Yin Yang 1. In contrast, SAA3 is a pseudogene, and SAA4 encodes a protein that is constitutively produced.
In mice, Saa1 and Saa2 are the primary forms of SAA produced by hepatocytes, while Saa3 encodes a functional SAA protein predominantly found in inflammatory tissues. Similar to humans, mouse Saa4 is expressed constitutively. The isoforms produced during APR are rapidly released into the bloodstream, where they are associated with high-density lipoproteins (HDL). This association affects SAA's role in lipid metabolism and immune response.
Cytokine-Like Properties of SAA
SAA exhibits a range of cytokine-like activities, initially identified through in vitro studies using recombinant human SAA (rhSAA). These studies revealed that rhSAA could induce chemotactic activity in blood neutrophils at concentrations achievable during APR. This chemotactic effect is mediated through the formyl peptide receptor 2 (FPR2), present on neutrophils and other phagocytic cells. Additionally, SAA has been shown to induce the expression of proinflammatory cytokines (e.g., TNF-α, IL-6, and IL-8) and anti-inflammatory cytokines (e.g., IL-10 and IL-1rn) in various immune cells.
A particularly intriguing aspect of SAA is its ability to skew macrophages towards an M2 phenotype, characterized by enhanced efferocytosis and the expression of M2 markers. This suggests that SAA's role extends beyond promoting inflammation to include regulatory and homeostatic functions.
Receptor Interactions and Signaling Pathways
SAA exerts its effects through interactions with various receptors. One primary receptor is FPR2 (formyl peptide receptor 2), a G protein-coupled receptor involved in chemotaxis and inflammation. RhSAA binding to FPR2 leads to NF-κB activation and an inflammatory response. Elevated FPR2 expression in conditions like rheumatoid arthritis and its role in neovascularization emphasize its significance in inflammation.
SAA also interacts with toll-like receptors (TLRs), particularly TLR2 and TLR4. Although SAA's structure differs from known bacterial ligands, it binds to TLR2/1 heterodimers, leading to MyD88-dependent signaling. This interaction activates ERK and p38 MAPK pathways, increasing cytokine production. TLR2's role in tumorigenesis through Stat3-dependent mechanisms further illustrates SAA's complex involvement in inflammation.
Additionally, SAA binds to scavenger receptors such as SR-BI and CLA-1, which are involved in cholesterol metabolism. These receptors mediate SAA-induced signaling, affecting MAPK activation and inflammatory responses. The ATP receptor P2X7 has also been implicated in SAA-induced NLRP3 inflammasome activation and antiapoptotic effects.
The diverse receptors and pathways activated by SAA reflect its multifaceted role in inflammation. SAA's ability to engage with different receptors and modulate various signaling pathways underscores its importance in both innate immune responses and broader inflammatory processes.
Unresolved Issues and Future Research Directions
Despite the advances in understanding SAA's role in inflammation, several issues remain unresolved. One major challenge is the difference between recombinant and native SAA isoforms. RhSAA, often used in research, may not fully replicate the properties of native SAA, particularly concerning receptor interactions and biological activities. The presence of LPS contamination in rhSAA preparations can further complicate results, as LPS itself can activate TLR4 and influence inflammatory responses.
Future research should focus on addressing these discrepancies by comparing the effects of rhSAA with native SAA isoforms in various experimental models. Advanced techniques, such as the use of transgenic mice and adenoviral vectors to express native SAA isoforms, could provide more accurate insights into SAA's functions. Additionally, controlling for LPS contamination and employing rigorous experimental controls will help ensure the reliability of findings.
Another area of interest is the potential dual role of SAA in inflammation. While SAA is known to be a potent proinflammatory mediator, its ability to induce both proinflammatory and anti-inflammatory cytokines suggests a more nuanced role. Research should investigate how SAA's effects vary in different inflammatory contexts and whether it acts as a modulator of inflammation rather than simply an inducer.
Conclusion
Serum Amyloid A (SAA) has emerged as a significant player in inflammation, with evidence suggesting that it may act as both a proinflammatory mediator and a homeostatic regulator. Its interactions with multiple receptors and signaling pathways highlight its complex role in the inflammatory process. While current research has expanded our understanding of SAA's functions, unresolved issues and discrepancies between recombinant and native SAA highlight the need for continued investigation.
Future research should aim to clarify the functional differences between rhSAA and native isoforms, address potential contaminants, and explore SAA's role in both acute and chronic inflammatory conditions. Advancing our knowledge of SAA's biological activities will enhance our ability to develop targeted therapies and improve our understanding of the acute-phase response.
References
- Sack Jr G. H. Serum amyloid A-a review. Molecular Medicine. 2018, 24 (1): 46.
- Ye R.D., Sun L. Emerging functions of serum amyloid A in inflammation. Journal of Leucocyte Biology. 2015, 98 (6): 923-929.
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