PT  - JOURNAL ARTICLE
AU  - Ryan Finethy
AU  - Jacob Dockterman
AU  - Miriam Kutsch
AU  - Nichole Orench-Rivera
AU  - Graham Wallace
AU  - Anthony S. Piro
AU  - Sarah Luoma
AU  - Arun K. Haldar
AU  - Seungmin Hwang
AU  - Jennifer Martinez
AU  - Meta J. Kuehn
AU  - Gregory A. Taylor
AU  - Jörn Coers
TI  - Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock
AID  - 10.1101/2020.03.18.997460
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.18.997460
4099  - http://biorxiv.org/content/early/2020/03/20/2020.03.18.997460.short
4100  - http://biorxiv.org/content/early/2020/03/20/2020.03.18.997460.full
AB  - Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-4. Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-4 are largely unknown. This study identifies dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) as negative regulators of caspase-4 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-4-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-4-mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-4 activation.