Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model
Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model
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DOI：
10.1007/s00441-021-03495-8
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发表时间：
2021-07
影响因子：
3.6
通讯作者：
Takashi Namba;O. Ichii;Teppei Nakamura;Md. Abdul Masum;Yuki Otani;M. Hosotani;Y. Elewa;Y. Kon
中科院分区：
文献类型：
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作者：
Takashi Namba;O. Ichii;Teppei Nakamura;Md. Abdul Masum;Yuki Otani;M. Hosotani;Y. Elewa;Y. Kon
IL-36亚家族属于IL-1家族，由激动剂(IL-36α、IL-36β、IL-36γ)和拮抗剂(IL-36Ra、IL-38)组成。我们先前报道了IL-36α在慢性肾炎小鼠肾小管中的过度表达。为了了解IL-36亚家族各成员在肾脏中的定位状况和生物学关系，采用病理学方法对MRL/MPJ-Faslpr/lpr小鼠作为自身免疫性肾炎模型进行了研究。MRL/MPJ-Faslpr/lpr小鼠发病时间为3个月，严重肾炎发病时间为6-7个月(分别为早期和晚期)。简言之，IL-36γ和IL-36ra在小鼠肾脏中有结构性表达，而在mRL/mpj-Faslpr/lprs小鼠中诱导表达IL-36α、IL-36β、IL-36ra和IL-38。IL-36α表达显著增加，并定位于损伤的肾小管上皮细胞。CD44+激活的壁上皮细胞(PECs)也表现出较高的IL-36α阳性率，尤其是在男性。IL-36β和IL-38表达于间质浆细胞。IL-36、α、IL-38定量指标与肾炎严重程度呈正相关。与IL-36α相似，IL-36Ra在晚期定位于TECs和PECs，而健康mRL/mpJ/mRL/mpJ小鼠在这两个时期的肾动脉中膜均有IL-36Ra阳性的平滑肌细胞。IL-36γ在肾交感神经轴突中呈结构性表达，与肾交感神经轴突分型和分期无关。IL-36受体基因在肾脏中普遍表达，且与病情严重程度成正比。MRL/mpj-Faslpr/lpr小鼠肾脏中IL-36下游候选分子显著上调，包括核因子-κB或丝裂原活化蛋白激酶途径组织分子。因此，IL-36亚家族有助于肾脏的动态平衡和炎症，尤其是以IL-36α为主的失衡可能强烈影响肾炎的恶化。
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-Faslpr/lprmice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Faslpr/lprmice 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-Faslpr/lprmice. 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-Faslpr/lprand 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-Faslpr/lprmice 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.