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Infarct macrophage secretome coordinates neutrophil degranulation
Author(s) -
Daseke Michael,
Kalusche Will,
Flynn Elizabeth,
Konfrst Shelby,
Lindsey Merry
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03172
Subject(s) - degranulation , fibronectin , chemistry , macrophage , immunology , microbiology and biotechnology , biology , extracellular matrix , biochemistry , in vitro , receptor
Following myocardial infarction (MI), the left ventricle undergoes wound healing that begins with an intense inflammatory response to recruit leukocytes to the infarcted region. Infiltrated neutrophils degranulate, releasing a series of proteases including matrix metalloproteinase (MMP)‐9 into the extracellular space. Macrophages also infiltrate into the infarct region, and we hypothesized that the macrophage may secrete factors that regulate neutrophil degranulation. Stimulating bone marrow derived neutrophils from C57BL/6J mice (3–6 month old male) with phorbol myristate acetate (PMA) induced degranulation, as evidenced by release of MMP‐9. Co‐stimulation with MI day 1 macrophage secretome (10% by volume) reduced PMA‐induced degranulation of MMP‐9 by 8‐fold (p<0.0014). Transcriptomics analysis of day 1 MI macrophages revealed galectin‐3, vimentin, fibronectin, and murinoglobulin‐1 were highly overexpressed. Examination of the day 1 MI macrophage secretome also showed high expression of vimentin and fibronectin. To further unmask signaling connections, neutrophils were co‐stimulated with PMA and day 1 MI macrophage secretome, along with blocking antibodies for the 4 proteins individually. Galectin‐3 or fibronectin inhibition promoted while murinoglobulin‐1 inhibition reversed the macrophage secretome effect. Neutrophil stimulation with recombinant galectin‐3 or fibronectin showed an additive effect with PMA on MMP‐9 release. Vimentin inhibition or stimulation had no effect on neutrophil degranulation. Overall, our results uncovered a role for galectin‐3 and fibronectin in inducing neutrophil degranulation while murinoglobulin‐1 may be a potent inhibitor of degranulation. The day 1 MI macrophage, therefore, secretes both factors that promote as well as factors that temper neutrophil degranulation. The balance of these factors determines the net effect of the macrophage secretome on neutrophil degranulation. Support or Funding Information NIH HL075360, HL129823, HL13731, VA 5I01BX000505.