NK-CD11c+ cell crosstalk in diabetes enhances IL-6-mediated inflammation during Mycobacterium tuberculosis infection.

Cheekatla S.S.; Tripathi, D.; Venkatasubramanian, S.; Pavan Kumar N.; Paidipally, P.; Ishibashi, M.; Welch, E.; Tvinnereim, A.R.; Ikebe, M.; Valluri, V.L.; Babu, S.; Kornfeld, H.; Vankayalapati, R.

PLoS Pathogens; 2016; 12; e1005972.   

Abstract: 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 Mtb infected 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. Further-more , 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.

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