The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Pathology
Animals; Chemokine CCL8; Gene Expression Regulation; Listeria monocytogenes; Listeriosis; Macrophages; Mice; Mice, Knockout; Neutrophils; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes; Transcription Factors; Transcription, Genetic
The transcriptional repressor B lymphocyte-induced maturation protein 1 (BLIMP1) is a master regulator of B and T cell differentiation. To examine the role of BLIMP1 in innate immunity, we used a conditional knockout (CKO) of Blimp1 in myeloid cells and found that Blimp1 CKO mice were protected from lethal infection induced by Listeria monocytogenes. Transcriptome analysis of Blimp1 CKO macrophages identified the murine chemokine (C-C motif) ligand 8, CCL8, as a direct target of Blimp1-mediated transcriptional repression in these cells. BLIMP1-deficient macrophages expressed elevated levels of Ccl8, and consequently Blimp1 CKO mice had higher levels of circulating CCL8, resulting in increased neutrophils in the peripheral blood, promoting a more aggressive antibacterial response. Mice lacking the Ccl8 gene were more susceptible to L. monocytogenes infection than were wild-type mice. Although CCL8 failed to recruit neutrophils directly, it was chemotactic for gamma/delta T cells, and CCL8-responsive gamma/delta T cells were enriched for IL-17F. Finally, CCL8-mediated enhanced clearance of L. monocytogenes was dependent on gamma/delta T cells. Collectively, these data reveal an important role for BLIMP1 in modulating host defenses by suppressing expression of the chemokine CCL8.
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Citation: J Immunol. 2014 Mar 1;192(5):2291-304. doi: 10.4049/jimmunol.1301799. Epub 2014 Jan 29. Link to article on publisher's site
Severa, Martina; Islam, Sabina A.; Waggoner, Stephen N.; Jiang, Zhaozhao; Kim, Nancy D.; Ryan, Glennice Bowen; Kurt-Jones, Evelyn A.; Charo, Israel; Caffrey, Daniel R.; Boyartchuk, Victor L.; Luster, Andrew D.; and Fitzgerald, Katherine A., "The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8" (2014). Infectious Diseases and Immunology Publications and Presentations. 182.