Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model

• Published in: Cell and tissue research Vol. 386; no. 1; pp. 59 - 77
• Main Authors: Namba, Takashi, Ichii, Osamu, Nakamura, Teppei, Masum, Md. Abdul, Otani, Yuki, Hosotani, Marina, Elewa, Yaser Hosny Ali, Kon, Yasuhiro
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2021; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Antagonists; Axons; B cells; Biomedical and Life Sciences; Biomedicine; CD44 antigen; Cytokines; Disease Models, Animal; Epithelial cells; Female; Homeostasis; Human Genetics; Interleukin 1; Interleukins; Interleukins - immunology; Kidney - pathology; Kidneys; Localization; Male; MAP kinase; Medical research; Medicine, Experimental; Mice; Molecular Medicine; Nephritis; Nephritis - immunology; NF-κB protein; Plasma cells; Proteomics; Regular Article; Renal Insufficiency, Chronic - immunology; Renal tubules; Smooth muscle; Systemic autoimmune disease; Nephritis; Chronic kidney disease; Interleukin 36; Inflammatory cytokine
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-021-03495-8

The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36α, IL-36β, IL-36γ) and antagonists (IL-36Ra, IL-38). We previously reported IL-36α overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ- Fas lpr/lpr mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ- Fas lpr/lpr mice exhibited disease onset from 3 months and severe nephritis at 6–7 months (early and late stages, respectively). Briefly, IL-36γ and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36α, IL-36β, IL-36Ra, and IL-38 was induced in MRL/MpJ- Fas lpr/lpr mice. IL-36α expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44 + -activated parietal epithelial cells (PECs) also exhibited higher IL-36α-positive rates, particularly in males. IL-36β and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36α and IL-38 positively correlated with nephritis severity. Similar to IL-36α, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ- Fas lpr/lpr and healthy MRL/MpJ mice possessed IL-36Ra + smooth muscle cells in kidney arterial tunica media at both stages. IL-36γ was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ- Fas lpr/lpr mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-κB- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36α-dominant imbalance could strongly impact nephritis deterioration.