Inflammasomes are multiprotein complexes involved in the activation of caspase-1 and the processing of the pro-inflammatory cytokines, interleukin (IL)-1b and IL-18 as well as the cell death mechanism of pyroptosis. The basic components of inflammasomes are a protease, caspase-1, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and a sensor molecule, e.g. a NOD-like receptor (NLR) such NLRP1, -2 or -3, AIM2 or pyrin. Inflammasomes are activated by DAMPs such as ATP, fatty acids, DNA or PAMPs as Bacillus anthracis or flagellin. However, some inflammasomes respond to more than one type of inflammasome inducer, e.g. the NLRP2 inflammasome is assembled in response to reactive oxygen species (ROS) or ATP. In addition, Pannexin 1 (Panx1) and the purinergic receptor P2X7 signaling pathways are involved in inflammasome regulation. Following activation, inflammasomes oligomerize to produce massive cytokine signaling platforms termed ASC specks. ASC specks are released into the extracellular space or into tissue fluids causing excessive inflammation leading to cellular and tissue damage.
InflamaCORE has an experienced team of scientists who are dedicated to the deep understanding of the innate immune response and how the inflammation can be targeted therapeutically. The company is on the verge of advancing an innovative treatment for acute neurological insults including stroke, brain trauma and spinal cord injury, as well as chronic CNS diseases like multiple sclerosis, Parkinson’s Disease and Alzheimer’s Disease, and also the development of diagnostic tests to diagnose early onset of disease, evaluate functional outcomes and help guide treatment strategies. The combination of novel therapeutic interventions targeting inflammasome activation and biomarker discovery provides a powerful approach to assess treatments in patients with these devastating injuries and diseases.
In the canonical pathway, the priming step involves the recognition of pathogen-associated molecular pattern (PAMP) or a danger-associated molecular pattern (DAMP) by a pattern recognition receptor (PRR) or Toll-like receptor (TLR), which recruits the adaptor protein myeloid differentiation primary response 88 (MYD88) into the receptor complex leading to phosphorylation of the inhibitor of nuclear factor-kB (NFkB) IkB through interaction with the p50 and p65 transcription factors. Activation of the NF-kB pathway causes the synthesis of pro-IL-1-b or pro-IL-18. NLRP3 is activated by lysosomal mediated cathepsin B via lysosome rupture, reactive oxygen species (ROS), oxidized mitochondrial (Mt) DNA, altered Ca2+ concentration via mitochondrial dysfunction, and adenosine triphosphate (ATP) efflux and potassium (K+) via pannexin1 (Panx1) channels. High extracellular ATP acts as a DAMP and binds to the purinergic receptor, P2X7 causing additional K+ efflux. Activation of NLRP3 involves oligomerization that results in activation of caspase-1 that converts pro-IL1b and pro-IL-18 into their mature forms. In addition, active caspase-1 cleaves Gasdermin D (GSDMD) into an N-terminus domain (GSDMD-N) and the autoinhibitory C-terminus domain (GSDMD-C). GSDMD-N binds to acidic phospholipids in the inner leaflet of the plasma membrane and oligomerizes to form pores that disrupt plasma membrane integrity, enabling release of IL-1b and IL-18 and inducing pyroptosis. The noncanonical pathway is activated by gram-negative bacteria or lipopolysaccharide (LPS) to activate caspase 4/5 in humans or caspase-11 in rodents that cleave GSDMD. The transient receptor protein channel 1 (TRPC1), a non-selective ion channel is also a substrate for caspase-11.
InflamaCORE was founded in 2009 with the vision of developing novel therapeutic interventions to target abnormal inflammation following CNS injury and repair. This starter company was formed by several University of Miami Miller School of Medicine faculty interested in the pathophysiology of treatment of brain and spinal cord injury. Over the last several years, InflamaCORE has made significant progress in clarifying the role of the innate immune response in the pathogenesis of CNS injury. Our scientists have discovered the molecular basis for abnormal inflammasome activation after different types of CNS injury and disease including multiple sclerosis, stroke, traumatic brain injury and spinal cord injury. InflamaCORE has developed novel biologics that target the adaptor protein ASC present in multiple inflammasomes and ASC specks that contribute to a variety of innate immune inflammatory diseases and conditions. Blocking inflammasome assembly and ASC speck function will prevent damaging inflammation in a variety of diseases and conditions.
"A Company Dedicated to Diagnosing and Treating Inflammatory Diseases"