Mouse IL17ra blocking peptide

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45(-)CD31(-)CD29(+)mEF-SK4(+)PDGFR(+)Sca-1(+)periostin(+) (Sca-1(+)) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1(+)periostin(+) cardiac fibroblasts (Postn(Cre)Il17ra(fl/fl)) protected mice from post-infarct heart failure and death. Moreover, Postn(Cre)Il17ra(fl/fl) mice had significantly fewer GM-CSF-producing Sca-1(+) cardiac fibroblasts and inflammatory Ly6C(hi) monocytes in the heart. Sca-1(+) cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1(+) cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

PURPOSE. T(H)17 cells play an important role in host defense and autoimmunity yet very little is known about the role of IL17 in herpes simplex virus (HSV)-1 infectivity. To better understand the relationship between IL17 and HSV-1 infection, we assessed the relative impact of IL17A-deficiency and deficiency of its receptors on HSV-1 responses in vivo. METHODS. We generated IL17RA(-/-) and IL17RA(-/-) RC-/- mice in-house and infected them along with IL17RA(-/-) and IL17RC(-/-) mice in the eyes with 2 x 10(5) PFU/eye of wild type (WI) HSV-1 strain McKrae. WT C57BL/6 mice were used as control. Virus replication in the eye, survival, corneal scarring (CS), angiogenesis, levels of latency-reactivation, and levels of CD8 and exhaustion markers (PD1, TIM3, LAGS, CTLA4, CD244, and CD39) in the trigeminal ganglia (TG) of infected mice were determined on day 28 postinfection. RESULTS. No significant differences in virus replication in the eye, survival, latency, reactivation, and exhaustion markers were detected among IL17A(-/-), IL17RA(-/-), IL17RC(-/-), IL17RA(-/-), and WT mice. However, mice lacking IL17 had significantly less CS and angiogenesis than WT mice. In addition, angiogenesis levels in the absence of IL17RC and irrespective of the absence of IL17RA were significantly less than in IL17A- or IL17RA-deficient mice. CONCLUSIONS. Our results suggest that the absence of IL17 protects against HSV-1-induced eye disease, but has no role in protecting against virus replication, latency, or reactivation. In addition, our data provide rationale for blocking IL17RC function rather than IL17A or IL17RA function as a key driver of HSV-1-induced eye disease.