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

PLoS Pathogens

Vijaya Lakshmi Valluri¹  Munenori Ishibashi²  Mitsuo Ikebe²  Hardy Kornfeld³  Ramakrishna Vankayalapati⁴  Amy R. Tvinnereim⁴  Deepak Tripathi⁴  Padmaja Paidipally⁴  Elwyn Welch⁴  Satyanarayana Swamy Cheekatla⁴  Sambasivan Venkatasubramanian⁴  Pavan Kumar Nathella⁵  Subash Babu⁵ 

[1] Blue Peter Research Center, LEPRA Society, Cherlapally, Hyderabad, India;Department of Cellular and Molecular Biology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America;Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States of America;Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America;National Institutes of Health, International Center for Excellence in Research, Chennai, India

关键词: Type 2 diabetes;    Mycobacterium tuberculosis;    Diabetes mellitus;    Mouse models;    Cytokines;    NK cells;    Tuberculosis;    Flow cytometry;   

DOI  :  10.1371/journal.ppat.1005972

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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. 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.

【 授权许可】

CC BY