Expression of SAA1, SAA2 and SAA4 genes in human primary monocytes and monocyte-derived macrophages

Abstract

Circulating serum amyloid A (SAA) is increased in various inflammatory conditions. The human SAA protein family comprises the acute phase SAA1/SAA2, known to activate a large set of innate and adaptive immune cells, and the constitutive SAA4. The liver synthesis of SAA1/SAA2 is well-established but there is still an open debate on extrahepatic SAA expression especially in macrophages. We aimed to investigate the ability of human primary monocytes and monocyte-derived macrophages to express SAA1 , SAA2 and SAA4 at both the transcriptional and protein levels, as previous studies almost exclusively dealt with monocytic cell lines. Monocytes and derived macrophages from healthy donors were stimulated under various conditions. In parallel with SAA , pro-inflammatory IL1A , IL1B and IL6 cytokine expression was assessed. While LPS alone was non-effective, a combined LPS/dexamethasone treatment induced SAA1 and to a lesser extent SAA2 transcription in human monocytes and macrophages. In contrast, as expected, pro-inflammatory cytokine expression was strongly induced following stimulation with LPS, an effect which was dampened in the presence of dexamethasone. Furthermore, in monocytes polarized towards a pro-inflammatory M1 phenotype, SAA expression in response to LPS/dexamethasone was potentiated; a result mainly seen for SAA1 . However, a major discrepancy was observed between SAA mRNA and intracellular protein levels under the experimental conditions used. Our results demonstrate that human monocytes and macrophages can express SAA genes, mainly SAA1 in response to an inflammatory environment. While SAA is considered as a member of a large cytokine network, its expression in the monocytes-macrophages in response to LPS-dexamethasone is strikingly different from that observed for classic pro-inflammatory cytokines. As monocytes-macrophages are major players in chronic inflammatory diseases, it may be hypothesized that SAA production from macrophages may contribute to the local inflammatory microenvironment, especially when macrophages are compactly organized in granulomas as in sarcoidosis.

miRNA/Target Gene Profile of Endothelial Cells Treated with Human Triglyceride‐Rich Lipoproteins Obtained after a High‐Fat Meal with Extra‐Virgin Olive Oil or Sunflower Oil

“…NF-kB2 is a subunit of NF-kB, which bound to RELA. Other possible predicted genes involved in proinflammatory response include interleukine 36 (IL-36), which is an emerging mediator of inflammatory disease, [38] serum amyloid A4 (SAA4), [39] and orosomucoid 1 (ORM1) and ORM2. [40] ORM1 has the capacity to induce release of interleukin 1 (IL-1), TNF , interleukin 6 (IL-6), and interleukin 12 (IL-12) [40] and inhibit injury-induced angiogenesis.…”

Serum Amyloid A Protein as a Potential Biomarker in predicting acute onset and association with in-hospital death in acute aortic dissection

“…Previous studies have indicated that HDL-C is negatively associated with cardiovascular risks, and low HDL-C levels may represent a high in-hospital mortality in AAD patients (28). SAA-HDL complex in blood has been demonstrated to have a high affinity for macrophages (14) and to further eliminate them from the blood in patients with sarcoidosis (29). Thus, increased SAA levels in AAD patients may be caused in response to the systemic inflammation, showing its potential value in predicting AAD characteristics.…”

Causes of AA amyloidosis: a systematic review

“…The production of SAA is regulated by cytokines such as interleukin-1 (IL1), interleukin-6 (IL6) and TNF, but also by glucocorticoids and lipopolysaccharide (LPS) [57]. The liver is the main site of SAA production, but monocyte-derived macrophages also can produce SAA [58]. Although chronically elevated SAA serum levels are a prerequisite, they are not sufficient alone to develop AA amyloidosis (Figure 2).…”

“…TBC, leprosy, rheumatoid arthritis, Whipple's disease, aspergillus infection, CVID, giant cell arteritis, Crohn's disease, sarcoidosis or Hodgkin's lymphoma) [43,63,64]. SAA production from macrophages might contribute to a local inflammatory microenvironment, especially when macrophages are compactly organized in granulomas [58]. Such a granulomatous disease process might somehow facilitate the development of the amyloid nidus as first hit.…”