Fellows’ research: New molecular mechanism uncovered that offers protection against autoimmune and autoinflammatory diseases
26 Feb 2019
Dr Santosh Chauhan, Intermediate Fellow
Institute of Life Sciences, Bhubaneshwar
In our recently published study, we showed how a protein called immunity-related GTPase M (IRGM) keeps inflammation under check by inhibiting the activation of inflammasome, a protein complex regulating inflammatory responses.
IRGM is both, genetically and functionally, linked with protection against several chronic inflammatory diseases including inflammatory bowel disease, Crohn's disease, leprosy, gastric cancer, chronic periodontitis, severe sepsis, and ankylosing spondylitis. The objective of this study is to define the mechanism by which IRGM is protective against these diseases. Understanding the mechanisms underlying the protective function of IRGM in inflammatory and autoimmune diseases will potentially pave the way for designing better-targeted therapeutic strategies.
Using cell culture and animal models, we defined a direct role of IRGM in suppressing NACHT, LRR, and PYD domains-containing protein 3 (NLRP3)-mediated inflammasome activation and in inflammatory diseases related to NLRP3. Dysregulation of NLRP3 and its mutations have been linked to many auto-inflammatory and autoimmune diseases, which are mostly characterized by increased production of interleukin 1 beta (IL-1β), an important mediator of the inflammatory response. We found that IRGM suppresses the production of IL-1β, by limiting the activation of the NLRP3 inflammasome. IRGM limits inflammasome activation by two mechanisms: (1) limiting assembly of inflammasome components and (2) mediating the autophagic-breakdown of inflammasome components. In an experimental mice model of Crohn’s disease, we observed that IRGM/Irgm1 protected from inflammation-induced cell death in addition to suppressing gut inflammation.
To design therapeutic strategies for autoimmune and inflammatory disorders/diseases, it is important to understand the mechanisms used by the cell to restrain immune response which occurs via NLRP3 inflammasome activation and IL-1β production. This study defines one of the important mechanisms by which IRGM suppress this activation. Currently, both chemical and biological strategies that increase IRGM activity, resulting in suppression of inflammasomes, are used for the treatment of inflammatory diseases. Strategies targeting the IRGM-NLRP3 interaction are under consideration as potential therapeutic interventions for IRGM- and NLRP3-associated diseases including Crohn’s disease.
The Crohn's disease risk factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy. Subhash Mehto, Kautilya Kumar Jena, Parej Nath, Swati Chauhan, Srinivasa Prasad Kolapalli, Saroj Kumar Das, Pradyumna Kumar Sahoo, Ashish Jain, Gregory A. Taylor, Santosh Chauhan. Molecular Cell. February 2019.
(Highlighted in the Issue 3 of Molecular Cell with a preview: Inflammasome inhibition links IRGM to innate immunity. Neel R. Nabar, John H. Kehrl)
Banner image credits: Dr Santosh Chauhan; Confocal imaging of inflammasome and components