Background/Purpose: Nerve injury-induced protein-1 (Ninj1) is an adhesion molecule that plays various roles in immune and stromal cells, including the modulation of inflammation and a critical role during cell death. Dysregulation of inflammatory pathways and cell death has been linked to the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Therefore, we hypothesized that Ninj1 may be involved in the pathogenesis of SLE.

Methods: Ninj1-deficient (Ninj1+/-) and wild-type (WT) C57/B6 mice were induced to develop lupus-like autoimmunity using two induced models triggered by topical application of the Toll-like receptor 7/8 (TLR7/8) agonist imiquimod (IMQ) or by intraperitoneal injection of pristane. We assessed the mice for clinical phenotype, immune dysregulation, and organ damage.

Results: In comparison to WT mice, Ninj1+/- mice exposed to IMQ exhibited greater splenomegaly at the expense of extramedullary hematopoiesis, more severe anemia, decreased spleen lymphocyte counts, and increased spontaneous neutrophil extracellular trap (NET) formation. Although we observed no differences in autoantibody levels or proteinuria, Ninj1+/- mice developed more lupus-associated renal disease, as evidenced by increased immune complex deposition and exacerbated kidney inflammation and damage. In the pristane model, Ninj1 deficiency worsened diffuse alveolar hemorrhage and lung inflammation. Furthermore, Ninj1+/- M2 bone marrow-derived macrophages (BMDM) exposed to IMQ in vitro showed defective activation of the p38/Erk 1/2 mitogen-activated protein kinase (MAPK) and Akt signaling pathways, which are important in M2 macrophage polarization.

Conclusion: Preliminary, these findings suggest that Ninj1 deficiency aggravates murine lupus, at least in part, by impairing the anti-inflammatory roles of M2 macrophages. Further experimentation is needed to identify the immune system defects associated with Ninj1 deficiency, particularly in the affected tissues, and to understand their implications for autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nerve-injury-induced-protein-1-ninj1-deficiency-aggravates-murine-lupus-through-modulation-of-macrophage-polarization/