MIF/CD74 axis participates in inflammatory activation of Schwann cells following sciatic nerve injury
- 7 Downloads
Based on deep RNA sequencing of distal segments of lesioned sciatic nerves, a huge number of differentially expression genes (DEGs) were thus obtained and functionally analyzed. The inflammatory response was denoted as one of most significant biological processes following sciatic nerve injury. In the present study, ingenuity pathway analysis (IPA) demonstrated that macrophage migration inhibitory factor (MIF) was identified as a core regulator of inflammatory response through interaction with CD74 membrane receptor. By establishment of rat sciatic nerve transection model, we displayed that MIF was upregulated following sciatic nerve axotomy, in colocalization with Schwann cells (SCs). MIF promoted migration, proliferation, together with inflammatory responses of SCs in vitro. Immunoprecipitation showed that MIF interacted with CD74 receptor, through which to activate intracellular ERK and JNK signaling pathways. Interference of CD74 receptor using specific siRNA showed that the transcription of proinflammatory cytokines including TNF-α, IL-1β, as well as cytokine receptor TLR4 in SCs was significantly attenuated, supporting an participation of MIF/CD74 signal axis in SCs inflammatory response. The data provide a novel role of MIF in eliciting inflammatory response of peripheral nerve injury, which might be beneficial for precise therapy of peripheral nerve inflammation.
KeywordsPeripheral nerve injury RNA sequencing Ingenuity pathway analysis Inflammatory response MIF Schwann cells
This study was supported by the Basic Scientific Research Projects of Nantong (JC2018065).
Compliance with ethical standards
Animal experiments were performed in strict accordance with the Institutional Animal Care guidelines.
- Benedek G, Meza-Romero R, Jordan K, Zhang Y, Nguyen H, Kent G, Li J, Siu E, Frazer J, Piecychna M, Du X, Sreih A, Leng L, Wiedrick J, Caillier SJ, Offner H, Oksenberg JR, Yadav V, Bourdette D, Bucala R, Vandenbark AA (2017) MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc Natl Acad Sci USA. 114(40):E8421–E8429CrossRefGoogle Scholar
- Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13(5):587–596CrossRefGoogle Scholar
- Bombeiro AL, Santini JC, Thomé R, Ferreira ER, Nunes SL, Moreira BM, Bonet IJ, Sartori CR, Verinaud L, Oliveira AL (2015) Enhanced immune response in immunodeficient mice improves peripheral nerve regeneration following axotomy. Front Cell Neurosci 10:151Google Scholar
- Fagone P, Mazzon E, Cavalli E, Bramanti A, Petralia MC, Mangano K, Al-Abed Y, Bramati P, Nicoletti F (2018) Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences. J Neuroimmunol 322:46–56CrossRefGoogle Scholar
- Lang T, Lee JPW, Elgass K, Pinar AA, Tate MD, Aitken EH, Fan H, Creed SJ, Deen NS, Traore DAK, Mueller I, Stanisic D, Baiwog FS, Skene C, Wilce MCJ, Mansell A, Morand EF, Harris J (2018) Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat Commun 9(1):2223CrossRefGoogle Scholar
- Lue H, Kapurniotu A, Fingerle-Rowson G, Roger T, Leng L, Thiele M, Calandra T, Bucala R, Bernhagen J (2006) Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal 18(5):688–703CrossRefGoogle Scholar
- Mangano K, Mazzon E, Basile MS, Di Marco R, Bramanti P, Mammana S, Petralia MC, Fagone P, Nicoletti F (2018) Pathogenic role for macrophage migration inhibitory factor in glioblastoma and its targeting with specific inhibitors as novel tailored therapeutic approach. Oncotarget 9(25):17951–17970CrossRefGoogle Scholar
- Merk M, Zierow S, Leng L, Das R, Du X, Schulte W, Fan J, Lue H, Chen Y, Xiong H, Chagnon F, Bernhagen J, Lolis E, Mor G, Lesur O, Bucala R (2011) The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). Proc Natl Acad Sci U S A 108(34):E577–E585CrossRefGoogle Scholar
- Mitchell RA, Metz CN, Peng T, Bucala R (1999) Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J Biol Chem 274(25):18100–18106CrossRefGoogle Scholar
- Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH, Collins MJ, Harrisingh MC, White IJ, Woodhoo A, Lloyd AC (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73(4):729–742CrossRefGoogle Scholar
- Presti M, Mazzon E, Basile MS, Petralia MC, Bramanti A, Colletti G, Bramanti P, Nicoletti F, Fagone P (2018) Presti M Overexpression of macrophage migration inhibitory factor and functionally-related genes, D-DT, CD74, CD44, CXCR31 and CXCR31, in glioblastoma. Oncol Lett 16(3):2881–2886Google Scholar
- Shin YK, Jang SY, Yun SH, Choi YY, Yoon BA, Jo YR, Park SY, Pak MG, Park JI, Park HT (2017) Cooperative interaction of hepatocyte growth factor and neuregulin regulates Schwann cell migration and proliferation through Grb2-associated binder-2 in peripheral nerve repair. Glia. 65(11):1794–1808CrossRefGoogle Scholar
- Wang L, Sanford MT, Xin Z, Lin G, Lue TF (2015) Role of Schwann cells in the regeneration of penile and peripheral nerves. Asian J Androl 17(5):776–782Google Scholar
- Yu J, Gu X, Yi S (2016) Ingenuity pathway analysis of gene expression profiles in distal nerve stump following nerve injury: insights into Wallerian degeneration. Front Cell Neurosci 10:274Google Scholar