Interdependence between Interleukin-1 and Tumor Necrosis Factor Regulates TNF-Dependent Control of Mycobacterium tuberculosis Infection

• Type of Material: Article
• Authors: Nelson Di Paolo, Emory University; Shahin Shafiani, Center for Infectious Disease Research; Tracey Day, Center for Infectious Disease Research; Thalia Papayannoupoulou, University of Washington; David W. Russell, University of Washington; Yoichiro Iwakura, University of Tokyo; David Sherman, Center for Infectious Disease Research; Kevin Urdahl, Center for Infectious Disease Research; Dmitry Shayakhmetov, Emory University
• Language: English
• Date: 2015-12-15
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.immuni.2015.11.016
• Title of Journal or Parent Work: Immunity
• ISSN: 1074-7613
• Volume: 43
• Issue: 6
• Start Page: 1125
• End Page: 1136
• Grant/Funding Information: This study was supported by the Grand Challenges Explorations grant from the Bill and Melinda Gates Foundation #51778, NIH grants AI065429, AI107960, and Children’s Healthcare of Atlanta (CHOA) Research Trust support to DMS, NIH U19 AI106761 and AI076327 and the Paul G. Allen Family Foundation grants to KU.
• Keywords: FAMILY; IL-1-ALPHA; Science & Technology; MICE DEFICIENT; IMMUNE-RESPONSE; Life Sciences & Biomedicine; CD4 T-CELLS; IN-VIVO; Immunology; INNATE; IDENTIFICATION; RECEPTOR
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

Abstract

The interleukin-1 receptor I (IL-1RI) is critical for host resistance to Mycobacterium tuberculosis (Mtb), yet the mechanisms of IL-1RI-mediated pathogen control remain unclear. Here, we show that without IL-1RI, Mtb-infected newly recruited Ly6Ghi myeloid cells failed to upregulate tumor necrosis factor receptor I (TNF-RI) and to produce reactive oxygen species, resulting in compromised pathogen control. Furthermore, simultaneous ablation of IL-1RI and TNF-RI signaling on either stroma or hematopoietic cells led to early lethality, indicating non-redundant and synergistic roles of IL-1 and TNF in mediating macrophage-stroma cross-talk that was critical for optimal control of Mtb infection. Finally, we show that even in the presence of functional Mtb-specific adaptive immunity, the lack of IL-1α and not IL-1β led to an exuberant intracellular pathogen replication and progressive non-resolving inflammation. Our study reveals functional interdependence between IL-1 and TNF in enabling Mtb control mechanisms that are critical for host survival.