The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6

Abstract

The matricellular protein CCN1 (CYR61) is known to function in wound healing and is upregulated in colons of patients with Crohn’s disease and ulcerative colitis, yet its specific role in colitis is unknown. Here we have used Ccn1dm/dm knockin mice expressing a CCN1 mutant unable to bind integrins α6β1 and αMβ2 as a model to probe CCN1 function in dextran sodium sulfate (DSS)-induced colitis. Ccn1dm/dm mice exhibited high mortality, impaired mucosal healing, and diminished IL-6 expression during the repair phase of DSS-induced colitis compared to wild type mice, despite having comparable severity of initial inflammation and tissue injury. CCN1 induced IL-6 expression in macrophages through integrin αMβ2 and in fibroblasts through α6β1, and IL-6 promoted intestinal epithelial cell (IEC) proliferation. Administration of purified CCN1 protein fully rescued Ccn1dm/dm mice from DSS-induced mortality, restored IEC proliferation and enhanced mucosal healing, whereas delivery of IL-6 partially rectified these defects. CCN1 therapy accelerated mucosal healing and recovery from DSS-induced colitis even in wild type mice. These findings reveal a critical role for CCN1 in restoring mucosal homeostasis after intestinal injury in part through integrin-mediated induction of IL-6 expression, and suggest a therapeutic potential for activating the CCN1/IL-6 axis for treating inflammatory bowel disease.

The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway

“…However, we observed reduced IL-6 in Aim2 −/− mice during the peak of the disease at day 7, which is in agreement with a protective role for IL-6 in IECs during colitis (Figure 2m). 56, 57, 58 In contrast, IL-18 was reduced at all time points (Figure 2m), in agreement with impaired inflammasome activation reminiscent of Asc −/− mice. 20, 21, 59 …”

CCN1/CYR61-mediated meticulous patrolling by Ly6C low monocytes fuels vascular inflammation

“…Therefore, platelets have at least three functions in our model: (i) recruitment of Ly6C low monocytes; (ii) commitment to meticulous patrolling of Ly6C low monocytes; and (iii) promotion of cytokine production by Ly6C low monocytes via direct interaction and/or release of CCN1. Matricellular protein CYR61/CCN1 has been studied extensively in cancer development and wound healing (15,16,47,48). In addition to confirming the chemoattractant properties of CCN1 on monocytes/macrophages (18, 20, 21), we also show that CCN1 sustains the patrolling of Ly6C low monocytes and is important for the initiation of inflammation.…”

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

“…The molecular functions of IL-6 in the intestine are complex and diverse 4. Besides various proinflammatory roles, there is recent evidence for a potent contribution of IL-6 to mucosal healing in acute intestinal lesions36 which might be in line with clinical experiences showing that inhibition of IL-6R signalling via tocilizumab in patients with rheumatoid arthritis was associated with a potent increase in risk of lower GI perforation 37. In addition to IL-6, various chemokines guiding neutrophil recruitment were found among the most upregulated genes in our NGS studies addressing targets of IL-36R signalling in colonic fibroblasts.…”