Graduate Research Assistant UT Hlth. San Antonio San Antonio, Texas, United States
Disclosure(s):
Natalie Six: No financial relationships to disclose
Introduction/Rationale: Systemic lupus erythematosus (SLE) is an autoimmune disease that features excessive immune activation and inflammation throughout the body. Local gut inflammation causes an impaired mucosal barrier (“leaky gut”), leading to the dissemination of gut bacteria and their immunogenic components throughout the body. SLE patients have elevated biomarkers of leaky gut; however, the mechanism by which this occurs is not clear.
Methods: To determine whether lupus-prone mice exhibit progressive defects in gut immune regulation, we performed flow cytometry on gut lamina propria cells of lupus-susceptible B6.Sle1.Sle2.Sle3 triple congenic (TC) mice and B6 controls at young, middle, and old ages. We also treated young TC, B6, and single congenic B6.Sle1 mice with two agents linked to lupus exacerbation and leaky gut: resiquimod (R848), a TLR7 agonist that mimics the high type I interferon signature seen in SLE patients, and Ruminococcus gnavus (Rg), a gut pathobiont that cross-reacts with anti-dsDNA autoantibodies.
Results: With age in TC mice, there were many immune alterations consistent with lupus progression, including increased CD4+ and CD8+ T cell frequencies. Notably, IL-22, a cytokine critical for gut barrier integrity and immune homeostasis, was depleted uniquely in the ileum of TC mice over time. ILC3s, the main immune cell subset responsible for producing IL-22 in the gut, correspondingly decreased with age in TC mice. Interestingly, R848 treatment in young TC mice reduced global IL-22 production and significantly altered the distribution of IL-22-producing cells. Combined Rg and R848 treatment in B6.Sle1 mice led to greater IL-22 depletion in ILC3s than R848 alone, indicating a synergistic mechanism between gut dysbiosis and TLR7 signaling, and increased IFN-y secretion, a strong inflammation marker.
Conclusion: Our findings demonstrate a gut-localized immune deficit in inducible models of lupus that mimics natural lupus progression and may precede or contribute to gut barrier vulnerability.
