Monitoring of inflammation using novel biosensor mouse model reveals tissue- and sex-specific responses to Western diet

Abstract

Obesity is an epidemic, and it is characterized by a state of low-grade systemic inflammation A key component of inflammation is the activation of inflammasomes, multiprotein complexes that form in response to danger signals and that lead to activation of caspase-1. Previous studies have found that a Westernized diet induces activation of inflammasomes and production of inflammatory cytokines. Gut microbiota metabolites, including the short-chain fatty acid butyrate, have received increased attention as underlying some obesogenic features, but the mechanisms of action by which butyrate influences inflammation in obesity remain unclear. We engineered a caspase-1 reporter mouse model to measure spatiotemporal dynamics of inflammation in obese mice. Concurrent with increased capsase-1 activation in vivo, we detected stronger biosensor signal in white adipose and heart tissues of obese mice ex vivo and observed that a short-term butyrate treatment affected some but not all the inflammatory responses induced by Western diet. Through characterization of inflammatory responses and computational analyses, we identified tissue- and sex-specific caspase-1 activation patterns and inflammatory phenotypes in obese mice, offering new mechanistic insights underlying the dynamics of inflammation.

Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses

“…To characterize global changes in inflammasome activation during aging, we used caspase-1 reporter mice described previously to visualize caspase-1 activation in vivo and ex vivo (37, 40, 41, 43). At ∼18 months of age, mice exhibited increased biosensor activation in vivo ( Fig 1A-B ), consistent with age-dependent increase in low-grade systemic inflammation.…”

“…Tissues were homogenized by electric homogenization in TRIzol TM (Invitrogen) and RNA was extracted following the manufacturer's instructions. cDNA was synthesized using the GoScript Reverse Transcription System (Promega) and quantitative real-time PCR was conducted as described previously (40).…”

“…To characterize global and tissue-specific changes in inflammasome activation during the process of aging, we utilized a transgenic mouse model in which a luciferase-based caspase-1 biosensor is constitively expressed in all tissues (37). Proteolytic activation of caspase-1 thus induces luciferase activation in specific tissues, allowing inflammasome activation to be monitored in vivo and ex vivo (37)(38)(39)(40)(41)(42)(43). These studies reveal a tissue-specific degree of overlap or discordance between age-associated inflammasome activation and upregulation of inflammatory transcripts commonly associated with inflammaging.…”

Programming Cell‐Derived Vesicles with Enhanced Immunomodulatory Properties

“…In the previous section, we demonstrate that membrane proteins anchored on MEVs play a vital role in MEV‐mediated M2 to M1 polarization. To identify membrane proteins that might enhance macrophage polarization in response to MEV delivery we used a computational pathway analysis protocol we developed and reported previously [ 24 ] ( Figure ). For this, we first hypothesized that M1‐derived MEVs contain significantly higher expression levels of proteins that support or suppress pathways associated with M1 versus M2 polarization.…”

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

“…To assess how changes in glucose homeostasis impact neuroinflammation, our study utilized mice expressing a caspase-1 biosensor to monitor inflammasome activation in the CNS [ 49 ]. We employed a modified cranial window technique on 5-week-old mice to allow visualization of biosensor activation in the brain [ 51 ].…”