Effector molecules involved in the regulation of gastrointestinal inflammation have been an area of intense research in the last decade.2
Of even greater interest are molecular pathways that might be shared between several immune-related diseases, such as asthma, obesity, and IBD.1,14-16
The role of Relm-α, a highly conserved Relm family member with a unique expression pattern mainly in alternatively activated macrophages, was unknown before our study.9,12
Herein we show that the major Relm-α+
population after DSS treatment is eosinophils. By generating Retnla−/−
mice, we define a critical role for this protein in mediating the cardinal features of experimental colitis and demonstrate a potent proinflammatory role for Relm-α through multiple independent approaches. Collectively, our data demonstrate a key role for Relm-α in colonic inflammation and a novel regulatory role for this molecule in the promotion of inflammation (). Given the unique function of Relm family members in experimental colitis, these results highlight that targeting Relm family members might be beneficial for immune modulation in patients with IBD. Nevertheless, given the potential metabolic roles of Relm family members, the exact settings in which such therapeutic intervention is desirable should be carefully addressed.
Our data demonstrate that Relm-α expression in the inflamed colon is markedly eosinophil derived. The differential expression pattern of Relm-α in myeloid cells compared with Relm-β, which is mainly expressed by epithelial cells,10,17
might explain the non-redundant roles of the Relm family members. Although Relm-β alone was sufficient only to induce TNF-α and IL-15 release from bone marrow–derived macrophages (of 22 measured cytokines),13
Relm-α did not induce cytokine secretion by itself but rather acted as a coactivator to amplify LPS-induced IL-6 and TNF-α secretion and regulate IL-10 levels. Thus Relm-α might regulate inflammatory processes by polarizing a proinflammatory rather than an anti-inflammatory response.
Recent findings demonstrate a proinflammatory role for eosinophils in DSS-induced colitis. In fact, eosinophil peroxidase has been shown to promote the pathogenesis of ulcerative colitis.18
Interestingly, eosinophil peroxidase can synergize with macrophage reactive oxygen species to kill tumor cells or potentially catalyze the oxidation of nitrite to generate additional cytotoxic radicals.19,20
Recent evidence suggests an active cross-talk between eosinophils and macrophages. Alternatively activated macrophages have a role in recruiting eosinophils after Nippostrongylus brasiliensis
infection, and we have recently detected eotaxin in human macrophages from patients with ulcerative colitis and in murine intestinal macrophages after DSS treatment.21,22
Furthermore, macrophages are a major source of TNF-α that can induce eosinophil activation and survival.23
Thus it is likely that eosinophil recruitment by macrophages can initiate a self-perpetuating cross-talk in the inflamed tissue in which macrophages are activated by eosinophil-derived products and vice versa
. However, similar to macrophages, eosinophils share the potential to promote tissue repair through multiple yet distinct pathways.24
For example, activated eosinophil numbers are higher in the quiescent phase of ulcerative colitis than in the active phase, and eosinophils have been linked to activation of fibroblasts to explain the phenomenon of fibrosis and stricture formation in Crohn disease.25
Taken together, our results highlight a new pathway in which eosinophils can amplify macrophage activation and perpetuate colonic inflammation.18,26
Future studies are required to shed more light on the eosinophil and macrophage interaction.
mice are also protected against DSS-induced colitis.10,13
Nevertheless, examination of Relm-β expression in Retnla−/−
mice revealed that Relm-β levels were intact at baseline and after DSS treatment. These data demonstrate that Relm-α and Relm-β independently and through distinct cell types contribute to eliciting intestinal inflammation (in the DSS-induced model). In agreement with this hypothesis and supporting a proinflammatory role for resistin and the Relm protein family are recent findings showing that resistin increases the production of TNF, IL-1, IL-6, and IL-12 and induces the activation of p38, extracellular signal-regulated kinase, and phosphatidylinositol 3-kinase.27,28
Resistin and Relm-β have been attributed important roles in glucose metabolism. It has been recently reported that transgenic mice overexpressing resistin exhibit impaired insulin-mediated glucose transport.29
Indeed, mice lacking resistin exhibit low blood glucose levels because of reduced hepatic glucose production.30
Furthermore, lack of resistin diminishes the increases in glucose levels that are associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.30
Moreover, infusion of Relm-β (or resistin) into rats decreased hepatic insulin sensitivity and was not attributed to peripheral insulin resistance.31
It is thus likely that Relm-α will possess similar activities as well.
In summary, our results define the involvement of Relm-α in colonic inflammation and highlight an eosinophil–Relm-α–macrophage axis. These results imply a similar role for Relm-α under other inflammatory conditions in which Relm-α and eosinophils are observed (eg, asthma). Furthermore, these results outline a novel innate immune pathway in which eosinophils have the potential to regulate immune polarization through regulating macrophage activation.
- Relm-α is expressed by intestinal eosinophils and epithelial cells and has a critical role in DSS-induced colitis.
- Relm-α promotes macrophage activation by synergizing with LPS to induce proinflammatory cytokine release and inhibit anti-inflammatory cytokines.