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2016 ; 10
(3
): e0004467
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IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury
in Orientia tsutsugamushi-Infected Mice
#MMPMID26943125
Shelite TR
; Liang Y
; Wang H
; Mendell NL
; Trent BJ
; Sun J
; Gong B
; Xu G
; Hu H
; Bouyer DH
; Soong L
PLoS Negl Trop Dis
2016[Mar]; 10
(3
): e0004467
PMID26943125
show ga
Endothelial cells (EC) are the main target for Orientia tsutsugamushi infection
and EC dysfunction is a hallmark of severe scrub typhus in patients. However, the
molecular basis of EC dysfunction and its impact on infection outcome are poorly
understood. We found that C57BL/6 mice that received a lethal dose of O.
tsutsugamushi Karp strain had a significant increase in the expression of IL-33
and its receptor ST2L in the kidneys and liver, but a rapid reduction of IL-33 in
the lungs. We also found exacerbated EC stress and activation in the kidneys of
infected mice, as evidenced by elevated angiopoietin (Ang) 2/Ang1 ratio,
increased endothelin 1 (ET-1) and endothelial nitric oxide synthase (eNOS)
expression. Such responses were significantly attenuated in the IL-33-/- mice.
Importantly, IL-33-/- mice also had markedly attenuated disease due to reduced EC
stress and cellular apoptosis. To confirm the biological role of IL-33, we
challenged wild-type (WT) mice with a sub-lethal dose of O. tsutsugamushi and
gave mice recombinant IL-33 (rIL-33) every 2 days for 10 days. Exogenous IL-33
significantly increased disease severity and lethality, which correlated with
increased EC stress and activation, increased CXCL1 and CXCL2 chemokines, but
decreased anti-apoptotic gene BCL-2 in the kidneys. To further examine the role
of EC stress, we infected human umbilical vein endothelial cells (HUVEC) in
vitro. We found an infection dose-dependent increase in the expression of IL-33,
ST2L soluble ST2 (sST2), and the Ang2/Ang1 ratio at 24 and 48 hours
post-infection. This study indicates a pathogenic role of alarmin IL-33 in a
murine model of scrub typhus and highlights infection-triggered EC damage and
IL-33-mediated pathological changes during the course of Orientia infection.
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