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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\u20101 and galectin\u20103, we identified several interacting pairs, such as CXCL12 and galectin\u20103. Based on NMR and MD studies of the CXCL12\/galectin\u20103 heterodimer, we identified contact sites between CXCL12 \u03b2\u2010strand 1 and Gal\u20103 F\u2010face residues. Mutagenesis of galectin\u20103 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin\u20103, but not its mutants, inhibited CXCL12\u2010induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin\u20103 attenuated CXCL12\u2010stimulated 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.<\/jats:p>","DOI":"10.15252\/embr.201947852","type":"journal-article","created":{"date-parts":[[2020,2,22]],"date-time":"2020-02-22T01:38:16Z","timestamp":1582335496000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Chemokines and galectins form heterodimers to modulate inflammation"],"prefix":"10.1038","volume":"21","author":[{"given":"Veit","family":"Eckardt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle C","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Blanchet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rundan","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Leberzammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3973-0022","authenticated-orcid":false,"given":"Johan","family":"Duchene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Soehnlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remco TA","family":"Megens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u2010Kristin","family":"Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelio","family":"Dregni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Faussner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanin","family":"Wichapong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Ippel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Dijkgraaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Kaltner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"D\u00f6ring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiril","family":"Bidzhekov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman M","family":"Hackeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Joachim","family":"Gabius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7474-9370","authenticated-orcid":false,"given":"Philipp","family":"von Hundelshausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin H","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"key":"BFEMBR201947852_CR1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1749-6632.2011.06291.x","volume":"1253","author":"D Cooper","year":"2012","unstructured":"Cooper D, Iqbal AJ, Gittens BR, Cervone C, Perretti M (2012) The effect of galectins on leukocyte trafficking in inflammation: sweet or sour? 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