Extracellular hsp70 release in Canine Steroid Responsive Meningitis-Arteritis

Abstract

The role of extracellular 70 kDa heat shock protein 70 (ehsp70) in central nervous system inflammation is vastly understudied, despite evidence supporting the ability to drive a pro-inflammatory state. We investigated the presence of ehsp70 in cerebrospinal fluid (CSF) and serum of dogs with Steroid Responsive Meningitis-Arteritis (SRMA), with the hypothesis that an ehsp70 response would occur, and might play a role in the pathogenesis of this disease. Samples from 30 dogs acutely affected with SRMA, and 30 dogs treated with corticosteroids and currently in clinical remission from SRMA were compared with normal dogs. Serum and CSF concentrations of ehsp70 were quantified using an enzyme-linked immunosorbent assay. An ehsp70 response occurred in the CSF of dogs with SRMA and this response was attenuated by corticosteroid treatment. There was no correlation between serum and CSF concentrations of ehsp70, supporting local production and release of ehsp70 and not simply leakage from serum. Dogs with SRMA thus represent a powerful spontaneous model by which to study the role of ehsp70 in CNS inflammation.

Virus-Heat Shock Protein Interaction and a Novel Axis for Innate Antiviral Immunity

“…Data from the ischemic-reperfusion injury model in dogs supports secretory release from within the CNS since hsp70 levels in serum was unaffected [92]. We have also observed increased levels of hsp70 in cerebrospinal fluid (and not serum) in steroid-responsive meningoarteritis in dogs [91], again supporting the potential role of extracellular hsp70 as a mediator of primary CNS inflammatory responses. Release of extracellular hsp70 in response to viral infection of the CNS has not been reported, and in no instance of CNS inflammatory disease has the form of hsp70 release been characterized.…”

“…Given the potential of hsp70 to stimulate innate immune responses, it is considered an alarm signal to neighboring cells in various kinds of pathophysiological environments including surgical stress, physical stress, ischemia, inflammation, and hyperthermia [87,88,89,90,91,92]. Release of hsp70 into cerebrospinal fluid (CSF) of the central nervous system (CNS) is an emerging field of research.…”

Involvement of the choroid plexus in the inflammatory response after acute spinal cord injury in dogs: An immunohistochemical study

“…To the authors’ knowledge, this is the first study demonstrating a potential role of the CP in the inflammatory response following acute SCI in the dog. IL-1β, TNF-α and hsp70 have all been previously implicated as potential mediators of CNS inflammation in acute SCI and immune-mediated inflammation (Wang et al, 2004; Sharma et al, 2006; Peng et al, 2009; Moore et al, 2012), and the pathologic significance of each of these molecules after SCI has been studied to various degrees. IL-1β and TNF-α responses have been documented in various pathologic conditions of the canine spinal cord, including chemically induced inflammation and ageing (Horais et al, 2003; Chung et al, 2010).…”

“…Additionally, laboratory models of SCI have repeatedly demonstrated IL-1β and TNF-α responses within the CNS, and improved outcome with attenuation of these responses (Wang et al, 2004; Peng et al, 2009; Sawai et al, 2010). Hsp70 responses have been less thoroughly evaluated; however, the inducible form of hsp70 is normally near the lower limit of detection by ELISA in the CSF of health dogs, and rises in conditions of cellular ischemia or inflammation (Awad et al, 2008; Moore et al, 2012). …”

“…In particular, we examined expression of IL-1β, TNF-α, and hsp70. These three proteins have been previously implicated as markers or mediators of a robust inflammatory response of the spinal cord following acute SCI, spinal cord ischemia-reperfusion (IR) injury and meningomyelitis (Sharma et al, 2006; Awad et al, 2008; Hecker et al, 2008; Peng et al, 2009; Moore et al, 2012). Particularly related to SCI, extracellular release of hsp70, IL-1β, and TNF-α may represent important contributors to inflammation, and likely inhibit recovery; IL-1β by exerting a direct detrimental effect (Allan et al, 2005), and TNF-α and hsp70 by serving as danger associated molecular patterns (DAMPs) and TLR agonists that stimulate further inflammatory cytokine release (Calderwood et al, 2007).…”