Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Abstract

Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic and physical insults that produce distinct types of inflammatory responses. This aetiologic view of inflammation informs its classification based on a cause‐dependent mechanism as well as a cause‐directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the centre of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non‐immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors’ access to the nucleus. We present two approaches that control proinflammatory signalling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signalling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell‐penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the nine genes required for metabolic responses. We compare these emerging anti‐inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical and other types of inflammation afflicting millions of people worldwide.

Protection from Endotoxin Shock by Selective Targeting of Proinflammatory Signaling to the Nucleus Mediated by Importin Alpha 5

“…Humans mount a systemic inflammatory response to as little as 2–5 ng of LPS per kilogram of body weight. This reaction evokes a 2-fold increase in the expression of 4533 genes in circulating leukocytes, a transcriptional response known as a “genomic storm.” LPS is one of the most proinflammatory virulence factors of Gram-negative bacteria (1, 2). These multidrug resistant pathogens typically cause lung infections, which often leads to sepsis and septic shock, especially in immunocompromised hosts (2).…”

“…This reaction evokes a 2-fold increase in the expression of 4533 genes in circulating leukocytes, a transcriptional response known as a “genomic storm.” LPS is one of the most proinflammatory virulence factors of Gram-negative bacteria (1, 2). These multidrug resistant pathogens typically cause lung infections, which often leads to sepsis and septic shock, especially in immunocompromised hosts (2). LPS recognition by its cognate receptor, TLR4, expressed on multiple cell types (including myeloid and lymphoid cells, vascular endothelial cells, and respiratory epithelial cells), triggers robust signaling to the nucleus mediated by a cascade of signal transducers (3, 4).…”

“…Exposing these “zip codes” for nuclear import enables instant recognition by the nuclear transport shuttles, importin α (Imp α ) and Imp β, thereby allowing nuclear translocation of SRTFs (5, 6). Thus, the nuclear transport system comprises the pivotal checkpoint for several transcriptional cascades (2).…”

“…Upon reaching the genome, SRTFs activate a myriad of genes that encode mediators of inflammation, such as cytokines, chemokines, cell-adhesion molecules (e.g., VCAM-1), and other intracellular signal transducers (2, 5). We have shown previously that this inflammatory genomic storm can be calmed by cell-penetrating peptides known as nuclear transport modifiers (NTMs), which target nuclear transport shuttles (7, 8).…”

“…Metabolic pathways are deranged in sepsis nonsurvivors (12). LPS also induces an unfolded protein response associated with endoplasmic reticulum stress (2) that activates Caspase 2-mediated processing of the main metabolic transcription factors, SREBPs. Deficiency of SREBP1a provided partial protection from endotoxin shock induced by a relatively low dose of LPS (13).…”