Identifying novel pathways at the interface of immunity and metabolism

Immunometabolic Pathways

Landos has applied its AI-based integrated computational discovery platform, focused on immunity and metabolism, to identify important new molecular targets. Through advanced computational modeling-based predictions of immune cell differentiation, tissue-level cellular interactions and molecular signaling cascades, Landos has projected the ability of key targets, NLRX1 and PLXDC2, to address multiple disorders linked to immune function.

The NLR (nucleotide-binding domain, leucine rich containing) family of proteins contributes to the regulation of innate and adaptive immunity. Landos has identified NLRX1 as a mitochondria-associated receptor, which serves to control and negatively regulate many of the processes induced by inflammasome activation. The effects of NLRX1 activation include decreased differentiation of effector CD4+ T cells and increased mitochondrial metabolism in immune cells. Furthermore, NLRX1 activation decreases NF-kappa B activity and a wide range of cytokines, including CD4+ T cells and those of myeloid origin.

PLXDC2 Pathway

The PLXDC2 pathway is a transmembrane receptor associated with immunoregulatory functions. Immunologically, PLXDC2 activation leads to the production of IL-10 and prevention of oxidative stress. PLXDC2 intercepts the receptor for advanced glycation end-products (RAGE) signaling pathway. This leads to downstream inhibition of NF-kappa B and HIF-1-alpha signaling that is associated with TNF-alpha, IL-6, MCP1 and other cytokines. Further supporting this anti-inflammatory cascade is an inhibition of the semaphorin 4A/plexin B1 axis that regulates MAPK activation. Through proteolysis of the VEGF receptor, activation of PLXDC2 can also induce anti-angiogenic effects that can limit immune cell infiltration and defects in tissue vascularization and anti-fibrotic effects that can reduce the production of fibronectin.