Necroptotic signaling is primed in Mycobacterium tuberculosis-infected macrophages, but its pathophysiological consequence in disease is restricted

Stutz, MD; Ojaimi, S; Allison, C; Preston, S; Arandjelovic, P; Hildebrand, JM; Sandow, JJ; Webb, AI; Silke, J; Alexander, WS; Pellegrini, M

Author(s): Stutz, MD; Ojaimi, S; Allison, C; Preston, S; Arandjelovic, P; Hildebrand, JM; Sandow, JJ; Webb, AI; Silke, J; Alexander, WS; Pellegrini, M;
Details: Publication Year 2017-12-11,Volume 25,Issue #5,Page 951-965
Journal Title: Cell Death and Differentiation
Publication Type: Journal Article
Abstract: Mixed lineage kinase domain-like (MLKL)-dependent necroptosis is thought to be implicated in the death of mycobacteria-infected macrophages, reportedly allowing escape and dissemination of the microorganism. Given the consequent interest in developing inhibitors of necroptosis to treat Mycobacterium tuberculosis (Mtb) infection, we used human pharmacologic and murine genetic models to definitively establish the pathophysiological role of necroptosis in Mtb infection. We observed that Mtb infection of macrophages remodeled the intracellular signaling landscape by upregulating MLKL, TNFR1, and ZBP1, whilst downregulating cIAP1, thereby establishing a strong pro-necroptotic milieu. However, blocking necroptosis either by deleting Mlkl or inhibiting RIPK1 had no effect on the survival of infected human or murine macrophages. Consistent with this, MLKL-deficiency or treatment of humanized mice with the RIPK1 inhibitor Nec-1s did not impact on disease outcomes in vivo, with mice displaying lung histopathology and bacterial burdens indistinguishable from controls. Therefore, although the necroptotic pathway is primed by Mtb infection, macrophage necroptosis is ultimately restricted to mitigate disease pathogenesis. We identified cFLIP upregulation that may promote caspase 8-mediated degradation of CYLD, and other necrosome components, as a possible mechanism abrogating Mtb's capacity to coopt necroptotic signaling. Variability in the capacity of these mechanisms to interfere with necroptosis may influence disease severity and could explain the heterogeneity of Mtb infection and disease.
Publisher: Springer Nature
Research Division(s): Infection And Immunity; Cell Signalling And Cell Death; Cancer And Haematology; Systems Biology And Personalised Medicine
PubMed ID: 29229989
Publisher's Version: https://doi.org/10.1038/s41418-017-0031-1
Open Access at Publisher's Site: https://doi.org/10.1038/s41418-017-0031-1
NHMRC Grants: NHMRC/1006592, NHMRC/1045549, NHMRC/1065626, NHMRC/1039014, NHMRC/1056282, NHMRC/1016647, NHMRC/1058344,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-01-15 09:30:04

Last Modified: 2018-07-09 03:28:23