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.