Association of TREM-1, IL-1β, IL-33/ST2, and TLR Expressions With the Pathogenesis of Ocular Toxoplasmosis in Mouse Models on Different Genetic Backgrounds

Abstract

Ocular toxoplasmosis (OT) is one of the most common causes of posterior uveitis. The signaling of triggering receptor expressed on myeloid cells (TREM)-1 amplifies inflammation, whereas TREM-2 signaling is anti-inflammatory. IL-1β is a major driver of inflammation during infection. Toll-like receptors (TLRs) play important roles in protective immune response during Toxoplasma gondii infection, and interleukin (IL)-33 receptor (T1/ST2) signaling prevents toxoplasmic encephalitis in mice. However, the pathogenic mechanisms of OT are not yet well elucidated. To investigate the role of TREM-1, TREM-2, IL-1β, IL-33/ST2, and TLRs in OT of susceptible C57BL/6 (B6) and resistant BALB/c mice, both strains of mice were intravitreally infected with 500 tachyzoites of the RH strain of T. gondii. Histopathological analysis showed that T. gondii-infected B6 mice had more severe ocular damage observed by light microscopy, higher number of neutrophil elastase-positive cells in the eyes detected by immunohistochemical staining, more T. gondii tachyzoites in the eyes observed by transmission electron microscopy, and higher mRNA expression levels of tachyzoite-specific surface antigen 1 detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in comparison of T. gondii-infected BALB/c mice. Detected by using qRT-PCR, the mRNA expression levels of TREM-1, IL-1β, IL-33, ST2, TLR11, TLR12, and TLR13 were significantly higher in the eyes of T. gondii-infected B6 mice than those of T. gondii-infected BALB/c mice, whereas the mRNA expression levels of TLR3 and TLR9 were significantly higher in the eyes of T. gondii-infected BALB/c mice than those of T. gondii-infected B6 mice. Correlation analysis showed that significant positive correlations existed between TREM-1 and IL-1β/IL-33/ST2/TLR9/TLR11 in the eyes of B6 mice and existed between TREM-1 and IL-33/ST2/TLR3/TLR9/TLR13 in the eyes of BALB/c mice after ocular T. gondii infection. Our data revealed that, compared with T. gondii-resistant BALB/c mice, ocular T. gondii infection can stimulate higher production of TREM-1, IL-33, ST2, TLR11, TLR12, and TLR13 in the eyes of T. gondii-susceptible B6 mice, however, whether those lead to more severe ocular pathology in the susceptible B6 mice remain to be further studied.

Keratinocytes and Activation of TREM-1 Pathway in Cutaneous Leishmaniasis Lesions

“…Studies have explored the role of TREM-1 in inducing inflammation in multiple contexts, such as sepsis [9,21], cancer [22], viral infections [23,24], and others non-infectious diseases [25,26]. However, the role of TREM-1 signaling in innate immunity against parasite infections and its underlying mechanisms remain unknown [13,27,28].…”

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications

“…Additionally, there was a significant correlation between the levels of IL-13 and ST2 and also the levels of IL-4 and ST2, suggesting that IL-33 signaling may be involved in the immunopathology of ocular toxoplasmosis (Tong and Lu, 2015). Higher levels of Il33 mRNA transcripts were also found in the eyes of Toxoplasma-infected susceptible C57BL/6 mice compared to resistant BALB/c mice; however, it was not clear whether this or other cytokines were responsible for the ocular pathology seen in C57BL/6 mice (Zhang et al, 2019).…”

“…Ocular toxoplasmosis can cause vision-threatening complications depending on the levels of inflammation. The action of IL-33 is important to control inflammation and pathology in the eye (Zhang et al, 2019). Kunming mice infected intraocularly with Toxoplasma showed increased numbers of IL-33 positive cells as well as higher levels of IL-33 and ST2 mRNA transcripts in the eyes and cervical lymph nodes.…”

“…Toxoplasma gondii T1/ST2 −/− BALB/c mice showed increased parasite burden in the brain Jones et al, 2010 Susceptible C57BL/6 mice showed increased IL-33 expression correlating with Th2 cytokines in an ocular model of toxoplasmosis Tong and Lu, 2015;Zhang et al, 2019 ST2 deficient C57BL/6 mice showed increased survivability in an oral model of toxoplasmosis Ryffel et al, 2019 Plasmodium spp. C57BL/6 mice show no difference in IL-33 expression 1.5 hours after P. berghei infection Mac-Daniel et al, 2014 Patients who died from P. falciparum infection showed significant IL-33 lung accumulation Ampawong et al, Leishmania spp.…”

The Functional Roles of IL-33/ST2 Axis in Ocular Diseases

“…The increased IL-33/ST2 signaling was closely related to the higher expression levels of these inflammatory mediators [ 97 ]. The same research group further revealed that in the damaged retina and choroid of OT mice, the mRNA levels of triggering receptor expressed on myeloid cells-1 and TLRs also significantly elevated and were positively correlated with the enhanced IL-33/ST2 signaling [ 98 ]. Therefore, current data indicates that IL-33/ST2 participates in the immune responses of OT and may exert its regulatory roles by indeterminate signaling pathways involving triggering receptor expressed on myeloid cells-1, TLRs, and Th1/Th2 cytokines.…”