Immune regulation via lectins
Bacterial glycans can be detected by lectins on immune cell surfaces as a major class of PRRs. C-type lectins, Siglecs, and galectins are three major lectin families104.
C-type lectin receptors (CLRs) bind carbohydrates in a Ca+2-dependent manner and can generate immune responses to pathogens105. In Peyer’s patches, macrophage inducible C-type lectin (Mincle) recognizes commensal bacteria in the mucosa106. This recognition induces expression of IL-6 and IL-23p19 and thereby regulates Th17 differentiation and IL-17 secretion (Fig. 1E)106. The same study demonstrated that Mincle deficient mice develop systemic translocation of the gut microbiota, for instance, Proteobacteria to the liver from the gut106. Helicobacter pylori(H . pylori ), a pathogen that colonizes gastric mucosa, was shown to interact with Mincle through its Lewis antigens of lipopolysaccharides (LPS) and cause an anti-inflammatory response to reside in the host107. H. pylori can also bind to DC-SIGN, a CLR, to evade immune responses by blocking the maturation of naive T-cells to Th1 cells (Fig. 2E)108.
Siglecs, Sialic acid-binding immunoglobulin-like lectins, are expressed on nearly all immune cells, and binding of bacterial products to these receptors may create both pro- and anti-inflammatory responses (Fig. 1F, Fig. 2F)109. For instance, Siglec-10 recognition ofCampylobacter jejuni (C. jejuni ) flagella promotes an anti-inflammatory response, thereby affecting functional properties of DCs and macrophages104,110.
Galectins, a family of lectins with an affinity for beta-galactosides, are expressed by immune cells, including natural killers (NKs), DCs, macrophages, and activated T- and B-cells111,112. Galectins can regulate adaptive immunity by influencing T-cell signaling and activation, and modulating immunosuppressive Treg function113. During infections, galectin expression can vary and interactions with bacteria and galectins can affect infection and sepsis114,115. Galectin-1 (Gal-1) dampens Th1 and Th17 mediated responses, creating a Th2 dominant immune response116-118. This effect is due to Th1 and Th17 cells expressing Gal-1 binding glycans; conversely, Th2 cells display α2,6-sialic acid-capped glycoproteins on their surfaces (Fig. 1F)119. A study utilizing a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model in mice demonstrated that treating with recombinant Gal-1 improved the disease outcome119. Recombinant Gal-1 diminishes the effects of TNBS related T-cells120. Galectin-3 (Gal-3) binds to the O-antigen side chains of H. pylori and helps it adhere to the gastric epithelia121. This interaction increases Gal-3 expression to allow phagocytic cells to traffic the infection sites121. Galectins can also recognize host glycans expressed on vacuoles that harbor intracellular pathogens and then induce autophagy122. A mouse study utilizing a Gal-3 knockout (KO) model demonstrated that when colitis was induced via dextran sulfate sodium administration, KO mice developed more severe colitis compared to wild-type littermates119. Treating the mice with Gal-3 ameliorated the effects of colitis119. A recent study demonstrated that Galectin-4 in intraepithelial lymphocytes coats cytosolicSalmonella enterica serovar Worthington, inducing bacterial chain and aggregate formation123. This process restricts bacterial motility and helps potentiate the inflammasome activation123. Chemotherapy treatments using agents like Fludarabine and Busulfan can lead to intestinal damage and result in increased T-cell activation and migration. Damaged organoids have been shown to possess increased Galectin-9, the key mediator for this chemotherapy-associated T cell activity (Fig. 2F)124.