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Small Heterodimer Partner Modulates Macrophage Differentiation during Innate Immune Response through the Regulation of Peroxisome Proliferator Activated Receptor Gamma, Mitogen-Activated Protein Kinase, and Nuclear Factor Kappa B Pathways
Zhang, Yuxia He, Lily Jones, Elizabeth Eppler, Natalie Ahamed, Forkan
Zhang, Yuxia
He, Lily
Jones, Elizabeth
Eppler, Natalie
Ahamed, Forkan
Abstract
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 Shp mRNA expression. Deletion of Shp promoted M1 differentiation while interfering with M2 polarization. Conversely, overexpression of SHP resulted in increased expression of peroxisome proliferator activated receptor gamma (Pparg), 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 Shp myeloid cell specific knockout (Shp-MKO). Concurrently, we observed significant induction of tumor necrosis factor alpha (Tnfa) and chemokine (C-C motif) ligand 2 (Ccl2) expression in LPS-treated Shp-MKO livers. Additionally, the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways were activated in LPS-treated Shp-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.
Keywords: nuclear receptor; small heterodimer partner (SHP); knockout; macrophage; differentiation
Description
A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.
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2023-08-28
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MDPI
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biomedicines-11-02403.pdf
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Ahamed, F.; Eppler, N.; Jones, E.; He, L.; Zhang, Y. Small Heterodimer Partner Modulates Macrophage Differentiation during Innate Immune Response through the Regulation of Peroxisome Proliferator Activated Receptor Gamma, Mitogen-Activated Protein Kinase, and Nuclear Factor Kappa B Pathways. Biomedicines 2023, 11, 2403. https://doi.org/10.3390/biomedicines11092403