title: The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses following stressor exposure.
abstract: Exposure to stressors or trauma in the absence of pathogenic challenge can stimulate a systemic sterile inflammatory response characterized by high concentrations of blood and tissue cytokines, chemokines, and danger associated molecular patterns (DAMPs) such as heat shock protein-72 (Hsp72), and uric acid. The signaling pathways responsible for these responses remain unclear, however, the inflammasome may play a role. In vitro, DAMPs are known to stimulate the inflammasome in the presence of LPS to activate caspase-1 which cleaves immature precursors of interleukin (IL)-1β and IL-18 into their mature releasable forms. Furthermore, in vivo neutralization of the LPS selectively attenuates the stress-induced increase in the inflammasome-dependent cytokines IL-1β and IL-18. Thus, the current experiments tested the hypothesis that inflammasome-mediated processes are necessary for a systemic stress-induced inflammatory response to an acute stressor. The data presented (1) establish that male F344 rats exposed to an acute severe stressor (100 tail shocks) have elevated plasma concentrations of inflammatory proteins (IL-1β, IL-18, IL-6, IL-10, and monocyte chemotactic protein (MCP)-1), and DAMPs (uric acid and Hsp72); (2) demonstrate that inhibiting caspase-1 in vivo, using the caspase-1 inhibitor ac-YVAD-cmk, attenuates stress-induced production of IL-1β, IL-18, and IL-6 in both the circulation and peripheral tissues; and (3) implicates the DAMPs uric acid and Hsp72 as important signals contributing to inflammasome-dependent inflammatory responses using a stepwise multiple regression. The results increase our mechanistic understanding of systemic sterile inflammatory responses, and provide novel evidence that the inflammasome may be an important pharmacological target for treatment of these conditions.
authors.affiliation: Department of Integrative Physiology and the Center for Neuroscience, University of Colorado at Boulder, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Maslanik
authors.forename: Lucas
authors.initials: L
authors.lastname: Mahaffey
authors.forename: Kate
authors.initials: K
authors.lastname: Tannura
authors.forename: Lida
authors.initials: L
authors.lastname: Beninson
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Greenwood
authors.forename: Monika
authors.initials: M
authors.lastname: Fleshner
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000187:drug effects / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000502:physiology; D018925:Chemokines / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins / Q000097:blood; D058847:Inflammasomes / Q000187:drug effects / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013315:Stress, Psychological / Q000276:immunology / Q000503:physiopathology*; D014527:Uric Acid / Q000097:blood
chemical_list: D061945:Caspase Inhibitors; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D016753:Interleukin-10; D014527:Uric Acid; D020170:Caspase 1