IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6-mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6R alpha (mIL-6R alpha) and gp130. Owing to the restricted expression of mIL-6R alpha, classical IL-6 signaling occurs only in a limited number of cells such as hepatocytes and certain leukocyte subsets. IL-6 also interacts with soluble IL-6R alpha proteins and these IL-6/soluble IL-6R alpha complexes can subsequently bind to membrane-bound gp130 proteins and induce signaling. Because gp130 is ubiquitously expressed, this IL-6 trans-signaling substantially increases the spectrum of cells responding to IL-6. In this study, we analyze the role of classical IL-6 signaling and IL-6 trans-signaling in the innate immune response of mice against Listeria monocytogenes infection. We demonstrate that L. monocytogenes infection causes profound systemic IL-6 production and rapid loss of IL-6R alpha surface expression on neutrophils, inflammatory monocytes, and different lymphocyte subsets. IL-6-deficient mice or mice treated with neutralizing anti-IL-6 mAb displayed impaired control of L. monocytogenes infection accompanied by alterations in the expression of inflammatory cytokines and chemokines, as well as in the recruitment of inflammatory cells. In contrast, restricted blockade of IL-6 trans-signaling by application or transgenic expression of a soluble gp130 protein did not restrain the control of infection. In summary, our results demonstrate that IL-6R alpha surface expression is highly dynamic during the innate response against L. monocytogenes and that the protective IL-6 function is dependent on classical IL-6 signaling via mIL-6R alpha. The Journal of Immunology, 2013, 190: 703-711.