Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 23, Issue 5, Pages 3402-3416Publisher
WILEY
DOI: 10.1111/jcmm.14236
Keywords
Mac-1; mindin; phagocytosis
Categories
Funding
- National Natural Science Foundation [81770548, 81770558, 81570496]
- 973 programs [2015CB553800]
- National Clinical Research Center for Digestive Diseases, Xi'an [2015BAI13B07]
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Mindin has a broad spectrum of roles in the innate immune system, including in macrophage migration, antigen phagocytosis and cytokine production. Mindin functions as a pattern-recognition molecule for microbial pathogens. However, the underlying mechanisms of mindin-mediated phagocytosis and its exact membrane receptors are not well established. Herein, we generated mindin-deficient mice using the CRISPR-Cas9 system and show that peritoneal macrophages from mindin-deficient mice were severely defective in their ability to phagocytize E coli. Phagocytosis was enhanced when E coli or fluorescent particles were pre-incubated with mindin, indicating that mindin binds directly to bacteria or non-pathogen particles and promotes phagocytosis. We defined that( 131)I-labelled mindin binds with integrin Mac-1 (CD11b/CD18), the F-spondin (FS)-fragment of mindin binds with the alpha(M) -I domain of Mac-1 and that mindin serves as a novel ligand of Mac-1. Blockade of the alpha(M) -I domain of Mac-1 using either a neutralizing antibody or si-Mac-1 efficiently blocked mindin-induced phagocytosis. Furthermore, mindin activated the Syk and MAPK signalling pathways and promoted NF-kappa B entry into the nucleus. Our data indicate that mindin binds with the integrin Mac-1 to promote macrophage phagocytosis through Syk activation and NF-kappa B p65 translocation, suggesting that the mindin/Mac-1 axis plays a critical role during innate immune responses.
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