Osteopontin as two‐sided mediator of intestinal inflammation

Abstract

Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN−/−) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN−/– mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 β and matrix metalloproteinases was found in acute colitis of OPN−/– mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN–/– mice showed increased serum levels of tumour necrosis factor (TNF)-α, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN−/– mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn’s disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.

Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

“…[36][37][38][39] Our findings suggest that the pathogenesis of acute colitis induced by DSS is different from that of these other inflammatory diseases, as it is a mucosal disease in which an intact mucosal epithelial barrier is required to combat intermittent bacterial influx. Therefore, in contrast to DSS-induced chronic colitis, in which OPN may induce polarization of the type 1 helper T-cell immune response to cause increased inflammation, 40 OPN may actually attenuate inflammation in DSS-induced acute colitis by contributing to the resolution of a deregulated innate immune response in the colon. Yet, there is a possibility that stimulation of adaptive immunity could account for some of the responses to bovine milk OPN administration.…”

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…However, studies addressing the role of Opn during DSS-induced colitis, another chemically induced model, have been contradictory (14,15,(60)(61)(62)(63). Opn deficiency in Black Swiss mice was protective (15), whereas Opn deficiency in C57BL/6 mice resulted in increased intestinal tissue destruction (60) (61) found that Opn was anti-inflammatory during acute DSS colitis but proinflammatory during chronic DSS colitis. We have not tested chronic DSS colitis; however, our studies on T-cell transfer chronic colitis showed that Opn expression by CD103 − DCs exacerbated disease.…”

Osteopontin Mediates Citrobacter rodentium-Induced Colonic Epithelial Cell Hyperplasia and Attaching-Effacing Lesions

“…While our group has shown that OPN Ϫ/Ϫ mice are more susceptible to DSS colitis, through a reduction in tumor necrosis factor-␣ and neutrophil recruitment, 10,12 other investigators found an opposite effect. 9 More recently, Heilmann et al 11 found that OPN Ϫ/Ϫ mice are more susceptible to acute challenge with DSS, associated with reduced IL-22 and macrophage activity but increased serum tumor necrosis factor-␣, while chronic DSS-induced colitis was reduced in these mice. This variability can be explained, at least in part, by the use of different mouse strains, OPN gene modification strategies, varying DSS doses, animal facility conditions, and treatment protocols.…”

“…5 Increased levels of OPN are described in both the serum and intestinal mucosa of patients with IBD and correlate with disease severity. 11,27 In these patients, OPN is produced by gut epithelia, IgG-producing plasma cells, and macrophages. 28,29 Increased OPN expression in areas of active inflammation suggests that OPN is involved in stimulating cytokine production that contributes to a T H 1-predominant adaptive immune response, as is observed in Crohn's disease.…”

“…One study suggested that lack of OPN has a protective effect, 9 whereas others reported a detrimental outcome during the acute phase 10 -12 and protection from chronic exposure to DSS. 11 This controversy prompted us to study an association between OPN and gut inflammation, using C. rodentium as a model of infectious colitis, to provide insight regarding the role of OPN in the pathogenesis of IBD.…”