Intestinal Epithelial Cell-Derived Semaphorin 7A Negatively Regulates Development of Colitis via αvβ1 Integrin

Abstract

The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (Mϕs) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI-anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL-10 production by intestinal Mφs to regulate intestinal inflammation. Sema7A-deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1+MHC class IIintF4/80hiCD11bhi Mφs as the main producers of IL-10 via αvβ1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by Mφs during interactions between IECs and Mφs. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10–blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through αvβ1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and Mφs.

Semaphorin 7a+ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1–induced Pulmonary Fibrosis

“…We have not explored the contribution of Sema 7a expression on other cells, such as macrophages and epithelial cells, both of which are important drivers of Sema 7a-mediated T-cell activation (6,8) and fibrosis (24,31). Our study does not determine the receptor through which Sema 7a affects TGF-b1-induced lung fibrosis, although we have previously shown that Sema 7a's effects on human fibrocytes and murine lung fibrosis occur in a b1 integrin-dependent manner (9).…”

“…Semaphorin 7A (Sema 7a) is a glycophosphatidylinositolanchored membrane protein that is required for axon track formation during embryonic development (4,5). Sema 7a also regulates inflammatory responses via stimulation of macrophage chemotaxis and cytokine production (6), dendritic cell migration and chemokine expression (7), modulation of T-cell function (6)(7)(8), and regulation of collagen production by fibrocytes (9). Hematopoietic expression of Sema 7a is sufficient to induce fibrosis in TGF-b1-induced murine lung fibrosis (9); however, the mechanism(s) mediating these effects remain unknown.…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…This is likely mediated, at least in part, through the Plexin C1 receptor ( Figure [ Plexin C1 itself propagates the infiltration of immune cells into sites of sterile pulmonary inflammation and also during Zymosan A-induced inflammation [38,39]. By contrast, Sema7A was also found to be protective during dextran sulfate sodium (DSS)-induced colitis, where it increased the production of the anti-inflammatory cytokine IL-10 through the anb1 integrin receptor [40]. Therefore, the action of Sema7A is likely to be dependent on the expression of its target receptors within specific organ systems.…”

Gene Expression of Semaphorin 7A During Osteogenic Differentiation in Human Dental Follicle Cells

“…Integrin are heterodimers composed of the a-and b-subunits. In intestinal macrophages, interaction between avb1-integrin and Sema 7A produces IL-10 31) . Sema 7A initiates T-cell-mediated inflammatory responses through 11-integrin via FAK and MAPK activation 32) .…”