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The role of Gr‐1 + cells and tumour necrosis factor‐ α signalling during Clostridium difficile colitis in mice
Author(s) -
McDermott Andrew J.,
Higdon Kathryn E.,
Muraglia Ryan,
ErbDownward John R.,
Falkowski Nicole R.,
McDonald Roderick A.,
Young Vincent B.,
Huffnagle Gary B.
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12425
Subject(s) - tumor necrosis factor alpha , clostridium difficile toxin a , cytokine , colitis , immunology , cxcl1 , necrosis , chemokine , biology , clostridium difficile colitis , clostridium difficile , microbiology and biotechnology , medicine , inflammation , pathology , antibiotics
Summary The host response to Clostridium difficile infection in antibiotic‐treated mice is characterized by robust recruitment of Gr‐1 + cells, increased expression of inflammatory cytokines including tumour necrosis factor‐ α ( TNF ‐ α ), and the development of severe epithelial damage. To investigate the role of Gr‐1 + cells and TNF ‐ α during C. difficile colitis, we treated infected mice with monoclonal antibodies against Gr‐1 or TNF ‐ α . Mice were challenged with vegetative cells of C. difficile strain VPI 10463 following treatment with the third‐generation cephalosporin ceftriaxone. Ceftriaxone treatment alone was associated with significant changes in cytokine expression within the colonic mucosa but not overt inflammatory histopathological changes. In comparison, C. difficile infection following ceftriaxone treatment was associated with increased expression of inflammatory cytokines and chemokines including Cxcl1 , Cxcl2 , Il1b , Il17f and Tnfa , as well as robust recruitment of Ly6C Mid Gr‐1 High neutrophils and Ly6C High Gr‐1 Mid monocytes and the development of severe colonic histopathology. Anti‐Gr‐1 antibody treatment resulted in effective depletion of both Ly6C Mid Gr‐1 High neutrophils and Ly6C High Gr‐1 Mid monocytes: however, we observed no protection from the development of severe pathology or reduction in expression of the pro‐inflammatory cytokines Il1b , Il6 , Il33 and Tnfa following anti‐Gr‐1 treatment. By contrast, anti‐ TNF ‐ α treatment did not affect Gr‐1 + cell recruitment, but was associated with increased expression of Il6 and Il1b . Additionally, Ffar2 , Ffar3 , Tslp , Tff and Ang4 expression was significantly reduced in anti‐ TNF ‐ α ‐treated animals, in association with marked intestinal histopathology. These studies raise the possibility that TNF ‐ α may play a role in restraining inflammation and protecting the epithelium during C. difficile infection.