IL-9 neutralizing antibody exacerbates early systemic lupus erythematosus in MRL/lpr mice by reducing IL-2 and regulatory T cells.
Background
Systemic lupus erythematosus (SLE) is a chronic, progressive autoimmune disease marked by systemic immune complex deposition and multi-organ involvement. Despite its severity, treatment options are limited compared to other autoimmune conditions like rheumatoid arthritis. While some SLE patients exhibit elevated CD4+IL-9+ T cells, secreted interleukin (IL)-9, and IL-9 messenger RNA, the precise role of IL-9 in SLE pathogenesis has been ambiguous due to its known dual pro- and anti-inflammatory effects in autoimmune contexts. Understanding IL-9's function could reveal novel therapeutic targets.
Study Design
Researchers utilized the MRL/lpr murine model of SLE to investigate IL-9's role. Mice were treated with an IL-9 neutralizing antibody from 6 to 12 weeks of age or from 6 to 18 weeks of age. An isotype control antibody served as the comparator. Key endpoints included immune cell expansion, systemic IL-2 levels, kidney IL-9+ type 2 innate lymphoid cells (ILC2s), and kidney regulatory T cells (Tregs). Additionally, a cohort received IL-2 supplementation during IL-9 blockade to assess its impact on Treg numbers and disease progression.
Results
IL-9 demonstrated a protective role in the early stages of SLE. Treatment with an IL-9 neutralizing antibody from 6 to 12 weeks of age resulted in a significant expansion of immune cells, leading to exacerbation of disease. In contrast, extending the anti-IL-9 treatment from 6 to 18 weeks of age did not significantly alter the disease course compared to the isotype control, suggesting a critical early window for IL-9's protective effects. Anti-IL-9 antibody treatment reduced systemic IL-2 levels, kidney IL-9+ type 2 innate lymphoid cells, and kidney regulatory T cells (Tregs). This indicates an IL-9-dependent suppressive cellular circuit. Importantly, IL-2 supplementation during IL-9 blockade successfully recovered regulatory T cell numbers and limited disease progression, highlighting the IL-9-IL-2-Treg axis.
These data collectively demonstrate an
IL-9-dependent suppressive circuit that is evident early in the development of SLE, which may be amenable to manipulation for therapeutic benefit.
Key Findings
- IL-9 neutralizing antibody treatment from 6 to 12 weeks exacerbated early SLE in MRL/lpr mice.
- Later IL-9 blockade (6 to 18 weeks) did not significantly alter disease course.
- IL-9 blockade reduced systemic IL-2 levels, kidney IL-9+ ILC2s, and kidney regulatory T cells.
- IL-2 supplementation during IL-9 blockade recovered Treg numbers and limited disease progression.
Why It Matters
This study reveals that IL-9 plays an early protective role in SLE by maintaining a suppressive immune circuit involving IL-2 and regulatory T cells. For peptide users and clinicians, this shifts the understanding of IL-9 from a potentially ambiguous cytokine to a crucial early protective factor. Manipulating the IL-9-IL-2 axis, particularly through strategies like IL-2 supplementation, could represent a novel therapeutic approach for early-stage SLE. This suggests that interventions targeting IL-9 or its downstream effects might need to be carefully timed, potentially focusing on early disease to prevent exacerbation rather than later stages. The findings open avenues for developing protocols that support this protective circuit.
systemic lupus erythematosus
sle
il-9
il-2
autoimmune
inflammation