Gp130 signaling promotes development of acute experimental colitis by facilitating early neutrophil/macrophage recruitment and activation.
IL-6 is known to play a crucial role in the pathogenesis of chronic intestinal inflammation by modulating T cell functions. In this study, we investigated the role of gp130, the common signal transducer for all IL-6 cytokines, in a murine model of acute T cell independent colitis to better characterize the impact of gp130 on innate immune cells and the early stages of inflammation. Experimental colitis was induced by dextran sulfate sodium treatment of mice with inducible systemic deletion of gp130 (MxCre/gp130(-/-)), macrophage/neutrophil-specific gp130-deficiency (LysCre/gp130(-/-)), or bone marrow chimeric mice and compared with wild-type controls (gp130(f/f)). Systemic deletion of gp130 (MxCre/gp130(-/-)) protected mice from severe colitis and wasting and attenuated the mucosal inflammatory infiltrate as well as local cytokine, chemokine, and adhesion molecule expression. Experiments in newly generated macrophage/neutrophil-specific gp130-deleted animals (LysCre/gp130(-/-)) and gp130 bone marrow chimeric mice, revealed a dual mechanism of proinflammatory effects mediated by gp130. Leukocyte recruitment was impaired in gp130-deleted animals and gp130-deleted recipients of wild-type bone marrow, demonstrating a central role of gp130-dependent signals in nonmyeloid cells for directing leukocytes to sites of inflammation, which was further confirmed in a model of sterile peritonitis. In contrast, macrophage/neutrophil-specific gp130 deficiency delayed and attenuated the disease but only marginally affected the inflammatory infiltrate, indicating a defective activation of mucosal leukocytes. We provide evidence that IL-6 cytokines acting via gp130 are required in the acute stages of intestinal inflammation by modulating the dynamics of innate immune cell recruitment and activation.
Sander
Leif E
LE
Department of Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
Obermeier
Florian
F
Dierssen
Uta
U
Kroy
Daniela C
DC
Singh
Anurag K
AK
Seidler
Ursula
U
Streetz
Konrad L
KL
Lutz
Holger H
HH
Müller
Werner
W
Tacke
Frank
F
Trautwein
Christian
C
D000208:Acute Disease; D000818:Animals; D002634:Chemotaxis, Leukocyte; D003092:Colitis / Q000209:etiology*; D050822:Cytokine Receptor gp130 / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007249:Inflammation; D015850:Interleukin-6 / Q000502:physiology; D008262:Macrophage Activation; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation; D015398:Signal Transduction / Q000276:immunology
D015850:Interleukin-6; D050822:Cytokine Receptor gp130