Macrophages in regulating intestinal barrier function
Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. In homeostatic conditions, macrophages are one of the most abundant intestinal immune cells. Intestinal macrophages inhabit the lamina propria and are involved in a variety of biological processes, including removal and degradation of microorganisms and tissue repair [42, 43]. Intestinal macrophages also limit inflammation, facilitate the survival of local FOXP3+ T regulatory cells and maintain epithelial integrity [44, 45]. Mouse intestinal macrophages express CD64, Mertk, CD11c, MHCII and F4/80 while human macrophages express CD64. Moreover, while in mice they are characterized by different subsets in the intestine, such as CD14hiHLA-DRloCD209loCD163lo, CD14hi/loHLA-DRhiCD209loCD163loCD11c+, CD14loHLA-DRhiCD209hiCD163hiand CD14hiHLA-DRhiCD209hiCD163hi, no significant functional differences have been observed [21, 23]. These populations are distinguished from dendritic cells by the expression of CD14 [23]. Intestinal macrophages localize closely with epithelial cells and disruption of this association results in loss of intestinal barrier function, as reported in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn’s disease [46]. Both epithelial and macrophage protein tyrosine phosphatase non-receptor type 2 is found to have an important role in facilitating the association of intestinal epithelial cells with macrophages to maintain intestinal barrier function [47]. However, the mechanisms by which macrophages regulate intestinal epithelial barrier function need further validations. A pro-inflammatory cytokine storm drives the recruitment of monocytes that polarize to M1 macrophages in intestinal tissues and release pro-inflammatory cytokines like TNF-α, interleukin (IL)-6, IL-1β and NO, which disrupt intestinal barrier function [48]. Pathogens cross the damaged intestinal epithelial cell barrier and stimulate macrophages to produce more pro-inflammatory cytokines, such as IL-1, IL-6, IL-18, transforming growth factor-α (TGF- β) and tumor necrosis factor-β (TNF-α) are released. These act on intestinal epithelial cells directly or indirectly, leading to the injury or necrosis or apoptosis of intestinal epithelial cells, disruption of the epithelial barrier and deregulation of tight junction proteins, as observed in IBD [49]. Similarly, macrophage exposure to lipids from a high fat diet restricted the uptake of apoptotic cells and induction of IL-10 [50]. This results in poor intestinal barrier repair and continued intestinal injury leading to gut leakage. Despite there being few available studies on the role of macrophages in upregulating tight junction proteins, macrophage released mediators like macrophage inhibitory factor and its receptor cluster of differentiation 74 (CD74) have been reported to play a major role in the maintenance of the intestinal barrier function [51, 52]. In a recent study, the sub-epithelial macrophages protected the distal colon epithelial cells from hazardous luminal fungal metabolites, thereby preventing gut leakage and maintaining the barrier function. In the absence of these macrophages, dysregulated intake of fungal products by the epithelial cells lead to apoptosis and subsequent loss of epithelial barrier integrity [44]. This study speculated that intestinal macrophages play a significant role in maintaining the barrier function. Patients with chronic ulcerative colitis (UC) who survive the acute stage, enter a proliferative response phase which is characterized by the presence of hyperplastic intestinal epithelial cells and fibroblasts. The intestinal epithelial stem cells migrate, proliferate and differentiate into absorptive enterocytes, mucus-secreting goblet cells, hormone-secreting enteroendocrine cells, and tuft cells in order to reconstitute the integrity of the junctional epithelium integrity. Epithelial repair during the proliferative phase may result in the complete restoration of gut barrier function. A proper re-epithelialization is frequently affected which can result in progression to the fibrotic phase of UC. However, there is more to explore to improve our understanding regarding the co-ordination of microbiota with macrophages and epithelial cells.