Murine cytomegalovirus downregulates interleukin-17 in mice with retrovirus-induced immunosuppression that are susceptible to experimental cytomegalovirus retinitis

Abstract

Interleukin-17 (IL-17), a proinflammatory cytokine produced by CD4+ Th17 cells, has been associated with the pathogenesis of several autoimmune diseases including uveitis. The fate of IL-17 during HIV/AIDS, however, remains unclear, and a possible role for IL-17 in the pathogenesis of AIDS-related diseases has not been investigated. Toward these ends, we performed studies using a well-established animal model of experimental murine cytomegalovirus (MCMV) retinitis that develops in C57/BL6 mice with retrovirus-induced immunosuppression (MAIDS). After establishing baseline levels for IL-17 production in whole splenic cells of healthy mice, we observed a significant increase in IL-17 mRNA levels in whole splenic cells of mice with MAIDS of 4-weeks (MAIDS-4), 8-weeks (MAIDS-8), and 10-weeks (MAIDS-10) duration. In contrast, enriched populations of splenic CD4+ T cells, splenic macrophages, and splenic neutrophils exhibited a reproducible decrease in levels of IL-17 mRNA during MAIDS progression. To explore a possible role for IL-17 during the pathogenesis of MAIDS-related MCMV retinitis, we first demonstrated constitutive IL-17 expression in retinal photoreceptor cells of uninfected eyes of healthy mice. Subsequent studies, however, revealed a significant decrease in intraocular levels of IL-17 mRNA and protein in MCMV-infected eyes of MAIDS-10 mice during retinitis development. That MCMV infection might cause a remarkable downregulation of IL-17 production was supported further by the finding that systemic MCMV infection of healthy, MAIDS-4, or MAIDS-10 mice also significantly decreased IL-17 mRNA production by whole splenic CD4+ T cells. Based on additional studies using IL-10 −/− mice infected systemically with MCMV and IL-10 −/− mice with MAIDS infected intraocularly with MCMV, we propose that MCMV infection downregulates IL-17 production via stimulation of suppressor of cytokine signaling (SOCS)-3 and interleukin-10.

Continued Decline of Aqueous Interleukin-8 After Multiple Intravitreal Injections of Ganciclovir for Cytomegalovirus Retinitis

“…7 Multiple intravitreal injections of ganciclovir or foscarnet appeared to be well tolerated and improvement of the retinitis was observed, either in AIDS patients 8,9 or in non-AIDS patients. 4,10 Previous studies implied that inflammation cytokines, including interleukin (IL)-2, [11][12][13][14] IL-4, 15 and IL-17, 16 may be involved in the development of CMVR by influencing the patient's susceptibility to it. However, to our knowledge, these previous studies about the relationship between inflammation cytokines and CMVR are generally based on animal or cell studies.…”

Primate neural retina upregulates IL-6 and IL-10 in response to a herpes simplex vector suggesting the presence of a pro-/anti-inflammatory axis

“…The most important biological activities of IL-10 include down-modulation of the inflammatory response, antiviral activity, and inhibition of cell growth (Ghasemi et al, 2012). IL-10 potentially inhibits the synthesis of many inflammatory cytokines including IL-1 (Rosenbaum and Angell, 1995), IL-2 (Tumpey et al, 1994), IL-6 (Tumpey et al, 1998), IL-8 (Yoshida et al, 2001), IL-17 (Blalock et al, 2013; Sarangi et al, 2008) and TNF-α (Rosenbaum and Angell, 1995). IL-10 has been identified as a key component involved in the control of HSV-1 induced stromal keratitis (Sarangi et al, 2008).…”

“…In the mouse retina, increased IL-10 expression was detected in photoreceptor and Muller cells and is thought to protect the neuroretinal cells from the toxic effects of pro-inflammatory cytokines during EAU (Lee et al, 2011). IL-10 production is stimulated in murine HSV-1 and mCMV retinitis and is believed to play a role in down regulation of pro-inflammatory cytokines and viral clearance (Blalock et al, 2013; Jost et al, 2014; Saitoh-Ishibashi et al, 2003). Since hrR3 induces uveitis in NHP but not in mice, it is not clear that data in mice are translatable to NHPs.…”

“…Transient inflammation (Ikeda et al, 2009), or the induction of Th2 cytokines including IL-10 (Bennett, 2003), following subretinal injection of lentiviral and AAV vectors has also been reported. Studies using a murine cytomegalovirus retinitis model and experimental autoimmune uveitis suggest that retinal cells may suppress intraocular inflammation via stimulation of suppressor cytokines such as IL-10, IL-27, and SOCS (Blalock et al, 2013; Lee et al, 2011). The findings that both IL-6 and IL-10 have been associated with various forms of inflammation in the neural retina raises the possibility that a pro-/anti-inflammatory axis exists and the severity of uveitis could depend on which of the axes is predominant.…”

Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression

“…We previously reported using the MAIDS model of experimental MCMV retinitis that suppressors of cytokine signaling (SOCS)1 and SOCS3 mRNAs are significantly stimulated to high amounts in MCMV-infected eyes (5), a finding that correlates with high frequency of retinitis. We also recently reported that SOCS1 and SOCS3 are significantly stimulated during MCMV infection of mouse macrophages (6).…”