Innate and adaptive immune cross-talk regulates intestinal macrophage activation and drives colitis in mice

Abstract

In the gastrointestinal tract, the immune system must protect against potential pathogens whilst preventing destructive inflammatory responses to the host commensal microlfora. This is achieved in part through a complex and active network of specialized immune cells and regulatory cytokines. Breakdown of this dynamic balance between immune response and regulation is likely to be a major contributor to Inflammatory Bowel Disease. The importance of regulatory populations of lymphocytes in maintaining intestinal immune homeostasis is well established, but the contribution of innate immune cells, particularly macrophages and dendritic cells (DCs), is less well understood. The cytokine TGF-β is central to the generation and function of immune regulatory cells, and is present at high levels in the intestinal lamina propria. TGF-β must be activated before it can signal, which is mediated by binding to αv integrins, followed by proteolysis or conformational changes. We have found that deletion of av integrins in DCs and macrophages causes colitis and autoimmunity in mice, and this is associated with loss of TGF-β dependent regulatory T cells (Tregs) and Th17 cells in this intestine. Based on these and other data, we have proposed a model in which αvβ8 integrin expressed by DCs binds and activates TGF-β during antigen presentation to T cells, promoting differentiation to Tregs and Th17 cells. In more recent work, we have focused on the contribution of av integrins to innate immune cell regulation. Macrophages and DCs from av-knockout mice appear to be ‘hyperactivated’ compared with controls, with increased levels of expression of activation markers such as co-stimulatory molecules. Consistent with this, innate immune proinflammatory cytokines are greatly increased in the intestine and systemic circulation. Macrophages and DCs from αv-deficient mice showed much stronger responses to microbial stimulation in culture and colitis in these mice was dependent on commensal bacteria, suggesting that the increased innate immune cell activation and inflammation in vivo was due to dis-regulated macrophage responses to the microbiota. However, this hyperactivation of macrophages does not appear to be a direct consequence of αv deletion in these cells, but is instead a result of combined stimulation by lymphocytes, microbial components and other innate immune cells. Using microarray analysis of colons and isolated macrophages, we are identifying gene expression changes that are induced by each of these stimuli to understand this ‘cross talk’ between innate and adaptive immunity in the intestinal lamina propria. Following these approaches we aim to determine the mechanisms by which macrophage activation is regulated in response to this complex environment and understand how failure of these mechanisms contributes to development of intestinal inflammation and inflammatory bowel disease.