(733.8) Sarcospan-deficient mice exhibit a heightened inflammatory phenotype under obesiogenic conditions

Poster Board Number: E275

Rhiannon Crawford (Florida State University), Isela Valera (Florida State University), Jose Pindado (Florida State University), Gisienne Reis (Florida State University), Aida Kahmini (Florida State University), Florence Mumbi (Florida State University), Kislay Parvatiyar (Tulane University School of Medicine ), Michelle Parvatiyar (Florida State University)

To study the metabolic consequences of sarcospan (SSPN-/-) deletion we subjected WT and SSPN-/- male mice to high fat diet (60% fat) for 4 months and compared them to mice fed standard chow diet (CD). SSPN-/- mice were partially protected from weight gain and additional studies were performed to understand the role SSPN plays in obesity-associated inflammation. Initial experiments examined innate immune activation of cultured bone marrow-derived macrophages (BMDM) obtained from CD SSPN-/- and WT mice. In response to B-DNA, Poly I:C and lipopolysaccharide (LPS), SSPN-/- BMDM generally exhibited a faster, more robust pro-inflammatory response (e.g. IL-6, IFN-β, TNF-α) compared to WT. We hypothesized that SSPN acts as negative regulator of the Type-I interferon response although the pathways involved are still being investigated. To determine whether cultured SSPN-/- BMDM obtained from HFD mice have a dysregulated Type-I interferon response - isolated, cultured BMDM were treated at time 0- with B-DNA, Poly I:C and LPS and cytokine production was monitored at 0-, 12-, 24- and 36-hours post-treatment. BMDM obtained from HFD SSPN-/- mice exhibited a more pronounced response compared to BMDM obtained from non-HFD mice. Blood serum collected from WT and SSPN-/- HFD and CD mice was analyzed by cytokine array for the presence of pro-inflammatory markers. Consistent with data obtained from BMDM suggesting heightened responsiveness, SSPN-/- HFD mice had significantly higher circulating levels of C-X-C motif chemokine ligand (CXCL10 and CXCL11), chemokine (C-C motif) ligand 2 (CCL2) and IFN-γ compared to WT HFD and SSPN-/- CD mice. CXCL10, secreted by several cell types in response to IFN-γ, was significantly higher in serum of SSPN-/- mice. CCL2 is primarily secreted by monocytes, macrophages and dendritic cells to recruit specific immune cells to sites of inflammation while CXCL10 and CXCL11 are validated biomarkers associated with heart failure and ventricular dysfunction. In summary, the significance of a heightened pro-inflammatory response in SSPN-/- mice is intriguing and remains to be elucidated.

AHA SDG #16SDG29120002 and FDOH James and Esther King Biomedical Research Program #21K12 (M.S.P)