Do antimicrobial peptides and complement collaborate in the intestinal mucosa?

Abstract

It is well understood that multiple antimicrobial peptides (AMPs) are constitutively deployed by the epithelium to bolster the innate defenses along the entire length of the intestines. In addition to this constitutive/homeostatic production, AMPs may be inducible and levels changed during disease. In contrast to this level of knowledge on AMP sources and roles in the intestines, our understanding of the complement cascade in the healthy and diseased intestines is rudimentary. Epithelial cells make many complement proteins and there is compelling evidence that complement becomes activated in the lumen. With the common goal of defending the host against microbes, the opportunities for cross-talk between these two processes is great, both in terms of actions on the target microbes but also on regulating the synthesis and secretion of the alternate family of molecules. This possibility is beginning to become apparent with the finding that colonic epithelial cells possess anaphylatoxin receptors. There still remains much to be learned about the possible points of collaboration between AMPs and complement, for example, whether there is reciprocal control over expression in the intestinal mucosa in homeostasis and restoring the balance following infection and inflammation.

Keywords: Paneth cell; anaphylatoxin; antimicrobial peptide; cathelicidin; colitis; defensin; intestine; lectin pathway.

Figure 1

Generalized depiction of AMP expression along the axes of the intestines. (A) Pattern of expression in the longitudinal axis, comparing the healthy (left) with inflamed (right) intestines. The thickness of the bar/triangle for each AMP roughly depicts the relative concentration of that particular AMP. For example, RegIIIα is found along the small intestine with highest levels in the ileum and low levels in the large intestine. α-Defensins are also predominantly expressed in the small intestine with levels corresponding with the increasing abundance of Paneth cells from the duodenum to ileum. The longitudinal distribution of complement has not been characterized. (B) The epithelium of the small intestine is organized into crypts and villi, or in the case of the large intestine, crypts, and surface epithelium (e.g., lacks villi), which create a vertical axis along which differentiating cells migrate. Some AMPs are secreted from different cell types along this axis. For example, β-defensins are secreted by goblet cells, Paneth cells, and enterocytes and thus are produced in locations along the crypt-villus axis.

Figure 2

Models speculating on reciprocal interactions between AMPs and complement expression in the intestines. The first model is inferred from the example of C5aR blocked mice showing deficiencies in skin AMPs. The others remain to be tested.