NK-CD11c+Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

作者：Cheekatla Satyanarayana Swamy; Tripathi Deepak; Venkatasubramanian Sambasivan; Nathella Pavan Kumar; Paidipally Padmaja; Ishibashi Munenori; Welch Elwyn; Tvinnereim Amy R; Ikebe Mitsuo; Valluri Vijaya Lakshmi; Babu Subash; Kornfeld Hardy; Vankayalapati Ramakrishna

来源：PLoS Pathogens, 2016, 12(10): e1005972.

DOI：10.1371/journal.ppat.1005972

In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro-and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute-and chronic-T2DM mice increased survival (to 100%) and reduced pro-and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtbinfected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro-and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.

• 出版日期2016-10