Background/Purpose: Systemic lupus erythematous (SLE) is a systemic autoimmune disease that interferon (IFN) signature involved in the progress. NLRP12 (NOD-like receptor family (NLR) pyrin domain containing 12) is a pyrin containing NLR protein that we had linked its new biological function to the cross-regulation of Toll like receptor (TLRs) and Rig-I like receptor (RIG-I) pathways. NLPR12 acts as an innate immune check-point in regulating type I IFNs expression. Since NLRP12 may participate in the pathogenesis of lupus, its role in lupus nephritis remained unknown.

Methods: Wild type C57BL/6J (The Jackson Laboratory) and Nlrp12^-/- mice in 12 -week-old age were injected intraperitoneally with a single dose of 500 μl of pristane (2,6,10,14-tetramethylpentadecane, TMPD), and samples were collected from 1^st, 3^rd, and 5^th months after injection. Serum were collected for evaluation autoantibodies, complement, and renal functions. Kidneys were checked with histological and immune cells evaluation.

Results: The pristane-treated Nlrp12^-/- mice had significantly amount of an anti-dsDNA autoreactive antibody in serum than that in WT mice during whole period (1^st, 3^rd and 5^th month, P < 0.001, 0.02, 0.04 respectively). The extent of IgG deposition in the glomerulus are very different in WT and Nlrp12^-/- mice (1^st, 3^rd and 5^th month, P < 0.001). Expansion of IgG deposition continued till 5^th month. At the following 3^rd and 5^th month, amount of serum C3 was gradually decreased and Nlrp12^-/- mice exhibited the moderately lower serum C3 level compared to the WT mice. The pristane treated Nlrp12^-/- mice had greater tubular IgG deposition than WT mice during the whole period. The histologic analysis revealed the morphological change of tubules, dilatation of tubules and loss of TBM integrity in the 3^rd month after pristane injection in Nlrp12^-/- mice, which were less severe in WT mice. In the pristane model, we found the glomerular ICs deposition occurred significantly from 3^rd and rise gradually to 5^th month and this aligned with CD11b⁺ and Ly6C⁺ cells recruitment suggesting the inflammatory responses in glomerulus. The periodic acid–Schiff (PAS) and H&E stain reveals the enlargement of glomerulus from 3^rd to 5^th month. Progressive expansion of PAS staining was observed in WT mice, with more profound mesangial proliferation, enlarged tuft with surrounding tubule epithelium effacement and dilation in Nlrp12^-/- mice. The histologic scoring revealed Nlrp12^-/- had more severe glomeruli damage associating with enlarged glomerulus area from 3^rd to 5^th month post pristane injection (P = 0.003 and 0.004). Similarly, the increase of mesangial index represents the mesangial expansion with their elevated serum creatinine, especially in Nlrp12^-/- mice of 5^th month supporting an evidence of deterioration of kidney function.

Conclusion: The deposition of IgG/ICs in the glomerulus causes a series of inflammatory reaction. In pristane lupus-like model, NLRP12 deficiency promotes the prolonged inflammatory response and enhanced systemic autoantibodies production which facilitate the structural damage among the tubules and glomeruli that cause kidney damage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nlrp12-deficiency-mice-present-severer-lupus-nephritis-in-a-pristane-induced-lupus-like-model/