Ahamed Forkan, Eppler Natalie, Jones Elizabeth, He Lily, Zhang Yuxia
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Biomedicines. 2023 Aug 28;11(9):2403. doi: 10.3390/biomedicines11092403.
Hepatic macrophages act as the liver's first line of defense against injury. Their differentiation into proinflammatory or anti-inflammatory subpopulations is a critical event that maintains a delicate balance between liver injury and repair. In our investigation, we explored the influence of the small heterodimer partner (SHP), a nuclear receptor primarily associated with metabolism, on macrophage differentiation during the innate immune response. During macrophage differentiation, we observed significant alterations in mRNA expression. Deletion of promoted M1 differentiation while interfering with M2 polarization. Conversely, overexpression of SHP resulted in increased expression of peroxisome proliferator activated receptor gamma (), a master regulator of anti-inflammatory macrophage differentiation, thereby inhibiting M1 differentiation. Upon lipopolysaccharide (LPS) injection, there was a notable increase in the proinflammatory M1-like macrophages, accompanied by exacerbated infiltration of monocyte-derived macrophages (MDMs) into the livers of myeloid cell specific knockout (-MKO). Concurrently, we observed significant induction of tumor necrosis factor alpha () and chemokine (C-C motif) ligand 2 () expression in LPS-treated -MKO livers. Additionally, the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways were activated in LPS-treated -MKO livers. Consistently, both pathways were hindered in SHP overexpression macrophages. Finally, we demonstrated that SHP interacts with p65, thereby influencing macrophage immune repones. In summary, our study uncovered a previously unrecognized role of SHP in promoting anti-inflammatory macrophage differentiation during the innate immune response. This was achieved by SHP acting as a regulator for the Pparg, MAPK, and NF-κB pathways.
肝巨噬细胞是肝脏抵御损伤的第一道防线。它们分化为促炎或抗炎亚群是维持肝损伤与修复之间微妙平衡的关键事件。在我们的研究中，我们探究了主要与代谢相关的核受体小异二聚体伴侣（SHP）在先天免疫反应期间对巨噬细胞分化的影响。在巨噬细胞分化过程中，我们观察到mRNA表达有显著变化。SHP的缺失促进了M1分化，同时干扰了M2极化。相反，SHP的过表达导致过氧化物酶体增殖物激活受体γ（Pparg）的表达增加，Pparg是抗炎巨噬细胞分化的主要调节因子，从而抑制M1分化。注射脂多糖（LPS）后，促炎的M1样巨噬细胞显著增加，同时单核细胞衍生巨噬细胞（MDM）向髓系细胞特异性敲除（-MKO）小鼠肝脏的浸润加剧。同时，我们在LPS处理的-MKO小鼠肝脏中观察到肿瘤坏死因子α（TNFα）和趋化因子（C-C基序）配体2（CCL2）表达的显著诱导。此外，丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）通路在LPS处理的-MKO小鼠肝脏中被激活。一致地，这两条通路在SHP过表达的巨噬细胞中受到阻碍。最后，我们证明SHP与p65相互作用，从而影响巨噬细胞免疫反应。总之，我们的研究揭示了SHP在先天免疫反应期间促进抗炎巨噬细胞分化方面以前未被认识的作用。这是通过SHP作为Pparg、MAPK和NF-κB通路的调节因子来实现的。
