Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice

• Published in: The Journal of immunology (1950) 2013-05, Vol.190 (9), p.4773-4785
• Main Authors: Waddell, Amanda, Ahrens, Richard, Tsai, Yi-Ting, Sherrill, Joseph D, Denson, Lee A, Steinbrecher, Kris A, Hogan, Simon P
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Chemokine CCL11 - genetics; Chemokine CCL11 - metabolism; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colon - metabolism; Colon - pathology; Eosinophils - metabolism; Eosinophils - pathology; Female; Gene Expression; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Intestinal Mucosa - metabolism; Intestines - pathology; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells - metabolism; Myeloid Cells - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200057

In inflammatory bowel diseases (IBDs), particularly ulcerative colitis, intestinal macrophages (MΦs), eosinophils, and the eosinophil-selective chemokine CCL11, have been associated with disease pathogenesis. MΦs, a source of CCL11, have been reported to be of a mixed classical (NF-κB-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-κB and STAT-6 pathways to the intestinal MΦ/CCL11 response and eosinophilic inflammation in the histopathology of experimental colitis is not yet understood. Our gene array analyses demonstrated elevated STAT-6- and NF-κB-dependent genes in pediatric ulcerative colitis colonic biopsies. Dextran sodium sulfate (DSS) exposure induced STAT-6 and NF-κB activation in mouse intestinal F4/80(+)CD11b(+)Ly6C(hi) (inflammatory) MΦs. DSS-induced CCL11 expression, eosinophilic inflammation, and histopathology were attenuated in RelA/p65(Δmye) mice, but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory MΦ recruitment or alter apoptosis, but did attenuate LPS-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80(+)CD11b(+)Ly6C(hi) inflammatory MΦs. Molecular and cellular analyses revealed a link between expression of calprotectin (S100a8/S100a9), Ccl11 expression, and eosinophil numbers in the DSS-treated colon. In vitro studies of bone marrow-derived MΦs showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-κB-dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-κB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD.