LCN2/中性粒细胞胶原酶相关的脂质结合蛋白24p3（脂质结合蛋白2）是一种分泌蛋白，作为哺乳动物的细菌抑制分子。在神经炎症应激条件下，活化的微胶质细胞和反应性星形胶质细胞会产生和分泌LCN2，导致神经元凋亡。然而，目前尚不清楚通过调节LCN2的产生和分泌能否最小化炎症应激和神经元丢失。在这里，我们首先证明了LCN2从受到脂多糖（LPS）炎症应激剂刺激的反应性星形胶质细胞分泌出来。值得注意的是，我们发现两种有效的条件可以导致反应性星形胶质细胞中诱导的LCN2水平降低：蛋白酶体抑制和巨噬细胞/自噬流的激活。机制上，蛋白酶体抑制通过在原代星形胶质细胞中抑制NFKB/NF-κB激活，即使在炎症应激条件下，也可以通过NFKBIA/IκBα稳定来降低Lcn2表达。相反，通过MTOR抑制激活自噬流可以通过前分泌降解来减少LCN2的细胞内水平。此外，我们证明LCN2的N末端信号肽对其分泌和降解至关重要，这表明这两个途径可能在机械上相互耦合。最后，我们观察到，在上述条件下，星形胶质细胞培养的介质中诱导的和分泌的LCN2水平降低，并导致神经元的生存能力增加，即使在炎症应激下仍然如此。简称：ACM，星形胶质细胞调节性介质；ALP，自噬溶酶体途径；BAF，巴非霉素A1；BTZ，波比星；CHX，环霉素；CNS，中枢神经系统；ER，内质网；GFAP，胶质纤维酸性蛋白；GFP，绿色荧光蛋白；JAK，贾纳斯激酶；KD，敲除；LCN2，脂质结合蛋白2；LPS，脂多糖；MACS，磁激活细胞分选；MAP1LC3/LC3，微管相关蛋白1轻链3；MTOR，雷帕霉素靶蛋白激酶；NFKB/NF-κB，B细胞中的kappa轻链多肽基因增强子1，p105；NFKBIA/IκBα，B细胞中的kappa轻链多肽基因增强子1抑制因子α；OVEX，过量表达；SLC22A17，溶质载体家族22成员17；SP，信号肽；SQSTM1，隔室1；STAT3，信号转导和转录激活因子3；TNF/TNF-α，肿瘤坏死因子；TUBA，α-管蛋白；TUBB3/β3-TUB，β3类III管蛋白；UB，泛素；UPS，泛素蛋白酶体系统。

LCN2/neutrophil gelatinase-associated lipocalin/24p3 (lipocalin 2) is a secretory protein that acts as a mammalian bacteriostatic molecule. Under neuroinflammatory stress conditions, LCN2 is produced and secreted by activated microglia and reactive astrocytes, resulting in neuronal apoptosis. However, it remains largely unknown whether inflammatory stress and neuronal loss can be minimized by modulating LCN2 production and secretion. Here, we first demonstrated that LCN2 was secreted from reactive astrocytes, which were stimulated by treatment with lipopolysaccharide (LPS) as an inflammatory stressor. Notably, we found two effective conditions that led to the reduction of induced LCN2 levels in reactive astrocytes: proteasome inhibition and macroautophagic/autophagic flux activation. Mechanistically, proteasome inhibition suppresses NFKB/NF-κB activation through NFKBIA/IκBα stabilization in primary astrocytes, even under inflammatory stress conditions, resulting in the downregulation of Lcn2 expression. In contrast, autophagic flux activation via MTOR inhibition reduced the intracellular levels of LCN2 through its pre-secretory degradation. In addition, we demonstrated that the N-terminal signal peptide of LCN2 is critical for its secretion and degradation, suggesting that these two pathways may be mechanistically coupled. Finally, we observed that LPS-induced and secreted LCN2 levels were reduced in the astrocyte-cultured medium under the above-mentioned conditions, resulting in increased neuronal viability, even under inflammatory stress.Abbreviations: ACM, astrocyte-conditioned medium; ALP, autophagy-lysosome pathway; BAF, bafilomycin A1; BTZ, bortezomib; CHX, cycloheximide; CNS, central nervous system; ER, endoplasmic reticulum; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; JAK, Janus kinase; KD, knockdown; LCN2, lipocalin 2; LPS, lipopolysaccharide; MACS, magnetic-activated cell sorting; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin kinase; NFKB/NF-κB, nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; NFKBIA/IκBα, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha; OVEX, overexpression; SLC22A17, solute carrier family 22 member 17; SP, signal peptide; SQSTM1, sequestosome 1; STAT3, signal transducer and activator of transcription 3; TNF/TNF-α, tumor necrosis factor; TUBA, tubulin, alpha; TUBB3/β3-TUB, tubulin, beta 3 class III; UB, ubiquitin; UPS, ubiquitin-proteasome system.