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.