Abstract
In vivo leukocyte recruitment is not fully understood and may result from interactions of chemokines with glycosaminoglycans/GAGs. We previously showed that chlorite-oxidized oxyamylose/COAM binds the neutrophil chemokine GCP-2/CXCL6. Here, mouse chemokine binding by COAM was studied systematically and binding affinities of chemokines to COAM versus GAGs were compared. COAM and heparan sulphate bound the mouse CXC chemokines KC/CXCL1, MIP-2/CXCL2, IP-10/CXCL10 and I-TAC/CXCL11 and the CC chemokine RANTES/CCL5 with affinities in the nanomolar range, whereas no binding interactions were observed for mouse MCP-1/CCL2, MIP-1α/CCL3 and MIP-1β/CCL4. The affinities of COAM-interacting chemokines were similar to or higher than those observed for heparan sulphate. Although COAM did not display chemotactic activity by itself, its co-administration with mouse GCP-2/CXCL6 and MIP-2/CXCL2 or its binding of endogenous chemokines resulted in fast and cooperative peritoneal neutrophil recruitment and in extravasation into the cremaster muscle in vivo. These local GAG mimetic features by COAM within tissues superseded systemic effects and were sufficient and applicable to reduce LPS-induced liver-specific neutrophil recruitment and activation. COAM mimics glycosaminoglycans and is a nontoxic probe for the study of leukocyte recruitment and inflammation in vivo.
Highlights
Chemokines are established central players in coordinating directional and selective leukocyte migration into tissues for immune regulation in physiology and pathologies, including inflammatory disorders, infection and cancer
We showed that COAM binds to mouse granulocyte chemotactic protein-2’’ (GCP-2)/CXCL6 with higher affinity than heparan sulphate and chondroitin sulphate and that the resulting in vivo recruitment of neutrophils partially explains host antiviral resistance
Two other mouse ELR+ CXC chemokines, KC/CXCL1 and macrophage inflammatory protein-2’’ (MIP-2)/CXCL2, and the mouse ELR2 CXC chemokines IP10/CXCL10 and inducible T cell a chemoattractant’’ (I-TAC)/CXCL11 efficiently bound to both COAM and heparan sulphate in a concentration-dependent manner (Fig. 1B–E)
Summary
Chemokines are established central players in coordinating directional and selective leukocyte migration into tissues for immune regulation in physiology and pathologies, including inflammatory disorders, infection and cancer. These chemotactic cytokines have emerged to constitute a large family of over 50 different members, all of which are characterized by their small sizes (,8 to 10 kDa) and related structures [1,2]. For most chemokines a further biological distinction can be made between homeostatic or constitutively expressed chemokines, and inflammatory or inducible chemokines The latter subclass is expressed by non-immune and immune cells upon induction by various stimuli, including cytokines, such as IL-1b, TNF-a and IFN-c, and microbialderived molecular patterns [4]. Among inflammatory chemokines the ELR+ CXC chemokines carry an NH2-terminal conserved
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