Deletion of Tmem268 in Mice Suppresses Anti-infectious Immune Responses by Downregulating CD11b Signaling

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2024 May 10

PMID 38730209

Authors

Mengyuan Duan

Xuan Zhang

Yaxin Lou

Jinqiu Feng

Pengli Guo

Shufang Ye

Ping Lv

Yingyu Chen

Affiliations

Soon will be listed here.

Abstract

Transmembrane protein 268 (TMEM268) is a novel, tumor growth-related protein first reported by our laboratory. It interacts with the integrin subunit β4 (ITGB4) and plays a positive role in the regulation of the ITGB4/PLEC signaling pathway. Here, we investigated the effects and mechanism of TMEM268 in anti-infectious immune response in mice. Tmem268 knockout in mice aggravated cecal ligation and puncture-induced sepsis, as evidenced by higher bacterial burden in various tissues and organs, congestion, and apoptosis. Moreover, Tmem268 deficiency in mice inhibited phagocyte adhesion and migration, thus decreasing phagocyte infiltration at the site of infection and complement-dependent phagocytosis. Further findings indicated that TMEM268 interacts with CD11b and inhibits its degradation via the endosome-lysosome pathway. Our results reveal a positive regulatory role of TMEM268 in β2 integrin-associated anti-infectious immune responses and signify the potential value of targeting the TMEM268-CD11b signaling axis for the maintenance of immune homeostasis and immunotherapy for sepsis and related immune disorders.

References

Schaller M, Hildebrand J, Shannon J, Fox J, Vines R, Parsons J . Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol. 1994; 14(3):1680-8. PMC: 358526. DOI: 10.1128/mcb.14.3.1680-1688.1994. View

Sun H, Hu L, Fan Z . β2 integrin activation and signal transduction in leukocyte recruitment. Am J Physiol Cell Physiol. 2021; 321(2):C308-C316. PMC: 8424673. DOI: 10.1152/ajpcell.00560.2020. View

Huang J, Lin C, Wu S, Chen W, Chu C, Brown G . CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway. PLoS Pathog. 2015; 11(7):e1004985. PMC: 4488469. DOI: 10.1371/journal.ppat.1004985. View

Perini E, Schaefer R, Stoter M, Kalaidzidis Y, Zerial M . Mammalian CORVET is required for fusion and conversion of distinct early endosome subpopulations. Traffic. 2014; 15(12):1366-89. DOI: 10.1111/tra.12232. View

Schittenhelm L, Hilkens C, Morrison V . β Integrins As Regulators of Dendritic Cell, Monocyte, and Macrophage Function. Front Immunol. 2018; 8:1866. PMC: 5742326. DOI: 10.3389/fimmu.2017.01866. View

Macpherson M, Lek H, Prescott A, Fagerholm S . A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis. J Biol Chem. 2011; 286(19):17303-10. PMC: 3089572. DOI: 10.1074/jbc.M110.182998. View

Rose D, Alon R, Ginsberg M . Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev. 2007; 218:126-34. DOI: 10.1111/j.1600-065X.2007.00536.x. View

Stearns-Kurosawa D, Osuchowski M, Valentine C, Kurosawa S, Remick D . The pathogenesis of sepsis. Annu Rev Pathol. 2010; 6:19-48. PMC: 3684427. DOI: 10.1146/annurev-pathol-011110-130327. View

Wu H, Rodgers J, Dai Perrard X, Perrard J, Prince J, Abe Y . Deficiency of CD11b or CD11d results in reduced staphylococcal enterotoxin-induced T cell response and T cell phenotypic changes. J Immunol. 2004; 173(1):297-306. DOI: 10.4049/jimmunol.173.1.297. View

10.

Iqbal A, Krautter F, Blacksell I, Wright R, Austin-Williams S, Voisin M . Galectin-9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin-dependent manner. FASEB J. 2021; 36(1):e22065. DOI: 10.1096/fj.202100832R. View

11.

Lamers C, Pluss C, Ricklin D . The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology. Front Immunol. 2021; 12:662164. PMC: 8118671. DOI: 10.3389/fimmu.2021.662164. View

12.

Moreno-Layseca P, Icha J, Hamidi H, Ivaska J . Integrin trafficking in cells and tissues. Nat Cell Biol. 2019; 21(2):122-132. PMC: 6597357. DOI: 10.1038/s41556-018-0223-z. View

13.

Han C, Jin J, Xu S, Liu H, Li N, Cao X . Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol. 2010; 11(8):734-42. DOI: 10.1038/ni.1908. View

14.

Toda G, Yamauchi T, Kadowaki T, Ueki K . Preparation and culture of bone marrow-derived macrophages from mice for functional analysis. STAR Protoc. 2021; 2(1):100246. PMC: 7797923. DOI: 10.1016/j.xpro.2020.100246. View

15.

Liew P, Kubes P . The Neutrophil's Role During Health and Disease. Physiol Rev. 2019; 99(2):1223-1248. DOI: 10.1152/physrev.00012.2018. View

16.

Brubaker S, Bonham K, Zanoni I, Kagan J . Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015; 33:257-90. PMC: 5146691. DOI: 10.1146/annurev-immunol-032414-112240. View

17.

Pruenster M, Kurz A, Chung K, Cao-Ehlker X, Bieber S, Nussbaum C . Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun. 2015; 6:6915. PMC: 4411303. DOI: 10.1038/ncomms7915. View

18.

Arnaout M . Biology and structure of leukocyte β integrins and their role in inflammation. F1000Res. 2016; 5. PMC: 5054827. DOI: 10.12688/f1000research.9415.1. View

19.

Ehlers M . CR3: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes Infect. 2000; 2(3):289-94. DOI: 10.1016/s1286-4579(00)00299-9. View

20.

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View