SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis

Wu, Yongjian1,2; Wang, Qiaohua1,2; Li, Miao3; Lao, Juanfeng1,2; Tang, Huishu1,2; Ming, Siqi4; Wu, Minhao1,2; Gong, Sitang5; Li, Linhai6; Liu, Lei; Huang, Xi1,2,6,7

2023-03-15

10.1172/JCI150224

JOURNAL OF CLINICAL INVESTIGATION   Impact Factor & Quartile

0021-9738

1558-8238

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-KB signaling activation 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.

SCI

English

Others

National Natural Science Foundation of China["82072062","82102249","82270016"] ; National Science and Technology Key Projects for Major Infectious Diseases[2017ZX10302301-002] ; Development Project of Foshan Fourth People's Hospital["FSSYKF-2020003","FSSYKF-2020017"] ; Natural Science Foundation of Guangdong Province[2023A1515030065] ; open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital[202301-102] ; high-level hospital project of Shenzhen Third People's Hospital[G2023001]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000959317400001

AMER SOC CLINICAL INVESTIGATION INC

CLINICAL MEDICINE

Web of Science

1.Sun Yat sen Univ, Affiliated Hosp 5, Ctr Infect & Immun, Zhuhai, Guangdong Provi, Peoples R China
2.Sun Yat sen Univ, Affiliated Hosp 5, Guangdong Prov Key Lab Biomed Imaging, Zhuhai, Guangdong Provi, Peoples R China
3.Sun Yat sen Univ, Affiliated Hosp 7, Sci Res Ctr, Shenzhen, Guangdong Provi, Peoples R China
4.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Affiliated Hosp 2, Shenzhen, Guangdong Provi, Peoples R China
5.Guangzhou Med Univ, Dept Gastroenterol, Guangzhou Women & Childrens Med Ctr, Guangzhou Inst Pediat, Guangzhou, Guangdong Provi, Peoples R China
6.Guangzhou Med Univ, Qingyuan Peoples Hosp, Affiliated Hosp 6, Qingyuan, Guangdong Provi, Peoples R China
7.Sun Yat sen Univ, Ctr Infect & Immun, Affiliated Hosp 5, 52 Meihua East Rd, Zhuhai 519000, Guangdong Provi, Peoples R China

Wu, Yongjian,Wang, Qiaohua,Li, Miao,et al. SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis[J]. JOURNAL OF CLINICAL INVESTIGATION,2023,133(6).

Wu, Yongjian.,Wang, Qiaohua.,Li, Miao.,Lao, Juanfeng.,Tang, Huishu.,...&Huang, Xi.(2023).SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis.JOURNAL OF CLINICAL INVESTIGATION,133(6).

Wu, Yongjian,et al."SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis".JOURNAL OF CLINICAL INVESTIGATION 133.6(2023).