Chemokines and galectins form heterodimers to modulate inflammation

Abstract

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

Galectin-1 and platelet factor 4 (CXCL4) induce complementary platelet responses in vitro

“…Given the preference of CXCL4 and gal-1 for sulfated glycans [ 21 , 61 ], it is conceivable that CXCL4 and gal-1 at least in part share negatively charged binding sites on the platelet surface. Alternatively, Gal-1 and CXCL4 might undergo heterophilic interactions, as was recently shown for Gal-3 and CXCL12 [ 38 ], leading to an altered preference for particular glycans.…”

“…Circulating levels of gal-3 correlated with thrombus size and genetic delection of gal-3 reduced thrombosis, which could in turn be rescued by exogenous gal-3 treatment [ 37 ]. In addition, gal-3 has recently been found to bind to the chemokine CXCL12, resulting in an inhibition of CXCL12’s chemotactic functions [ 38 ]. Interestingly, both gal-1 and gal-3 serve as binding partners for circulating coagulation factor VIII and von Willebrand Factor [ 12 , 13 ].…”

Structural insight into the binding of human galectins to corneal keratan sulfate, its desulfated form and related saccharides

“…Obviously, this contact pattern lets other functionally active regions remain accessible, e.g. for binding chemokines like CXCL12 45 or other galectin CRDs for heterodimerization 46 .

Figure 2 HSQC data of Gal-3 CRD in complex with KS.

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Pro4 prolyl peptide bond isomerization in human galectin-7 modulates the monomer-dimer equilibrum to affect function

“…Since galectins are at least bifunctional, they can engage in binding more than one partner. Cooperation between sites for glycan binding and for non-glycan contacts on the cell surface has been documented to occur with Ctx-B [87,88], providing us with an inspiring model, and, indeed, recently for Gal-3 when interacting with a glycan and the chemokine CXCL12 [89].…”