We observed that SAA1/2 and SAA3 are expressed in the intestinal epithelium, and that SAA protein is secreted into the gut lumen. Mice lacking functional SAA1/2 expression appeared to be more susceptible to DSS-induced colitis, which suggests that SAA production and secretion play a role in intestinal immune homeostasis. In vitro experiments showed that intestinal-epithelial SAA expression reduced the viability of co-cultured E. coli, suggesting that SAA may aid in the local clearance of bacteria. The expression of SAA 1/2 was increased in intestinal tissue biopsies of Crohn's Disease patients, suggesting that SAA is involved in the disease.
One of the major of higher organisms is the interaction with omnipresent bacteria. This is particularly important at mucosal surfaces, such as the intestinal epithelium, which can be colonized by large numbers of bacteria. The seemingly peaceful cohabitation of bacteria with their host represents a state of "controlled inflammation", in which the bacteria are prevented from gaining access to the body proper by an array of protective mechanisms. These include tight-junctions between epithelial cells [
30], a layer of mucus covering the epithelium [
19], secretion of Immunoglobulin-A [
20], and an array of bactericidic proteins, enzymes, and peptides [
19,
21‐
24]. Deficiencies in one or more of these mechanisms may cause the intestinal microflora to adopt an unfavorable species composition or increases the risk of penetration by bacteria of the intestinal mucosa. Inflammatory bowel disease pathogenesis is indeed related to mutations in mechanisms allowing sensing and killing of bacteria [
25,
26,
31].
We confirm previous reports of intestinal-epithelial expression of acute-phase SAA [
17,
32,
33]. We also observed significant expression of SAA3 in IEC of healthy mice, in agreement with recently published data [
34]. The presence of SAA3 in the epithelia is interesting, since this isoform was thought to be mainly expressed in macrophages [
35]. Intuitively, since SAA is generally considered pro-inflammatory [
12‐
14,
36], one would predict that lack of SAA would result in less severe DSS colitis. We have previously demonstrated that lack of another pro-inflammatory factor, osteopontin, protects from DSS-induced colitis [
28]. And yet, the DKO mice appeared to be more susceptible to DSS-induced colitis. One possible explanation is that SAA could help reduce bacterial growth near the intestinal epithelium. Recently, it was shown that plasma SAA interacts with E. coli, presumably by binding to OmpA (outer membrane protein A) in the cell wall, thereby facilitating internalization and destruction of the bacteria by neutrophils and macrophages [
15]. We observed that SAA overexpression in IEC significantly reduces survival of co-cultured E. coli. We are currently investigating the mechanism for the bactericidal effect of SAA. One possibility is that, as with neutrophils, intestinal epithelial cells internalize E. coli opsonized by SAA. IEC are capable of generating bacteriocidic reactive oxygen species [
37], and are also able to internalize E. coli via phagocytosis [
38]. We [
39] and others [
40‐
43] have demonstrated significant expression of a candidate phagocytic receptor, Scavenger Receptor BI (SR-BI), on the apical surface of IEC. In non-professional phagocytes, such as HEK-293 cells, SR-BI strongly promotes phagocytosis [
44]. As our group has shown, SR-BI also acts as a receptor for SAA [
45], and we are currently investigating the role of SR-BI/SAA in the phagocytosis of bacteria and uptake of LPS into IEC. Together, these data suggest a model in which intestinal epithelial expression of SAA protects from colitis by reducing bacterial load. We also observed that intestinal biopsies from Crohn's Disease patients showed increased SAA expression. Crohn's Disease is related to local defects in bacterial sensing and killing mechanisms [
25,
26,
31], and we speculate that SAA is upregulated in Crohn's Disease in an attempt to compensate for these defects and to protect the intestinal tissue. Detailed studies are required to test this hypothesis.
We have previously shown that DSS-induced colitis leads to a strong increase in circulating levels of acute-phase SAA [
27,
28], which is likely mainly derived from the liver. DSS-colitis is characterized by destruction of the intestinal epithelium, and is therefore expected to result in significant translocation of bacteria into the portal circulation. The first major organ that would encounter translocated gut bacteria is the liver. Thus, SAA would not merely be a marker for inflammation, but it could be secreted by the liver in large amounts in order to stem the spreading of translocated Gram-negative bacteria. Therefore, intestinal epithelial and hepatic SAA could act as a complementary, two-pronged mechanism of defense against intestinal Gram-negative bacteria.