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SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis
Yongjian Wu, … , Lei Liu, Xi Huang
Yongjian Wu, … , Lei Liu, Xi Huang
Published February 7, 2023
Citation Information: J Clin Invest. 2023;133(6):e150224. https://doi.org/10.1172/JCI150224.
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Research Article Infectious disease Inflammation

SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis

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Abstract

Uncontrolled inflammation occurred in sepsis results in multiple organ injuries and shock, which contributes to the death of patients with sepsis. However, the regulatory mechanisms that restrict excessive inflammation are still elusive. Here, we identified an Ig-like receptor called signaling lymphocyte activation molecular family 7 (SLAMF7) as a key suppressor of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes/macrophages was significantly elevated in patients with sepsis and in septic mice. SLAMF7 attenuated TLR-dependent MAPK and NF-κB signaling activation in macrophages by cooperating with Src homology 2–containing inositol-5′‑phosphatase 1 (SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor–associated factor 6 (TRAF6) to inhibit K63 ubiquitination of TRAF6. In addition, we found that tyrosine phosphorylation sites within the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 were indispensable for the interaction between SLAMF7, SHIP1, and TRAF6 and SLAMF7-mediated modulation of cytokine production. Finally, we demonstrated that SLAMF7 protected against lethal sepsis and endotoxemia by downregulating macrophage proinflammatory cytokines and suppressing inflammation-induced organ damage. Taken together, our findings reveal a negative regulatory role of SLAMF7 in polymicrobial sepsis, thus providing sights into the treatment of sepsis.

Authors

Yongjian Wu, Qiaohua Wang, Miao Li, Juanfeng Lao, Huishu Tang, Siqi Ming, Minhao Wu, Sitang Gong, Linhai Li, Lei Liu, Xi Huang

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Figure 3

SLAMF7 attenuates MAPK/NF-κB signaling pathways by activating SHIP1.

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SLAMF7 attenuates MAPK/NF-κB signaling pathways by activating SHIP1.
(A–...
(A–C) Phosphorylation of AKT (A), MAPKs (ERK, JNK, and p38) (B), and IKKα/β (C) in RAW-SLAMF7 versus RAW-vector cells was examined by Western blotting after LPS stimulation at the indicated time points. (D) WT and SLAMF7-KO BMDMs were challenged with LPS for the indicated durations, followed by Western blotting to determine the phosphorylation of MAPKs and AKT. (E and F) Protein levels of the NF-κB p65 subunit in nuclei and the cytosolic fraction of LPS-treated RAW-vector versus RAW-SLAMF7 cells (E) and WT versus SLAMF7-KO BMDMs (F). (G and H) mRNA expression of Tnf, Il1b, and Il6 in WT versus SLAMF7-KO BMDMs before treatment with an inhibitor targeting PI3K/Akt (Ly294002) (G) and NF-κB (JSH23) (H), followed by LPS stimulation for 6 hours. (I) mRNA expression of Eat2, Sap, and Ship1 in BMDMs after stimulation with rmSLAMF7, followed by LPS stimulation. (J and K) Immunoblot (IB) analysis of p-SHIP1 in RAW-vector versus RAW-SLAMF7 cells (J) and WT versus SLAMF7-KO BMDMs (K) stimulated with LPS for 0, 15, 30, and 60 minutes. (L) mRNA expression of Tnf, II1b, and Il6 in RAW264.7 cells after pretransfection with SHIP1 siRNA, followed by LPS stimulation for 6 hours. Data represent the mean ± SEM from at least 3 independent experiments. ns, not significant. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed, unpaired Student’s t test (I) and 1-way ANOVA (G, H, and L).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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