Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/β-catenin pathway

Abstract

Background: Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods: A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results: DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/β-catenin pathway. Conclusions: Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

Keywords

Sepsis / Dendritic cells / Immune tolerance / Matrix metalloproteinases / Signaling pathway / β-catenin / Nuclear factor kappa-B

References

[1] Wang LX, Ren C, Yao RQ, Luo YN, Yin Y, Wu Y, et al. Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells. Cell Mol Life Sci. 2021; 78: 8209-27.

[2] Zhang Y, Chen L, Luo Y, Wang K, Liu X, Xiao Z, et al. Pink1/parkin-mediated Mitophagy regulated the apoptosis of dendritic cells in sepsis. Inflammation. 2022; 45: 1374-87.

[3] Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016; 126: 23-31.

[4] Bouras M, Asehnoune K, Roquilly A. Contribution of dendritic cell responses to sepsis-induced immunosuppression and to susceptibility to secondary pneumonia. Front Immunol. 2018; 9: 2590.

[5] Venet F, Demaret J, Gossez M, Monneret G. Myeloid cells in sepsis-acquired immunodeficiency. Ann N Y Acad Sci. 2021; 1499: 3-17.

[6] Poehlmann H, Schefold JC, Zuckermann-Becker H, Volk HD, Meisel C.Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care. 2009; 13: R119.

[7] Du K, Hao S, Luan H. Expression of peripheral blood DCs CD86, CD80, and Th1/Th2 in sepsis patients and their value on survival prediction. Comput Math Methods Med. 2022; 2022: 4672535.

[8] Ghislat G, Cheema AS, Baudoin E, Verthuy C, Ballester PJ, Crozat K, et al. NF-κB-dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity. Sci Immunol. 2021; 6:eabg3570.

[9] Mulas F, Wang X, Song S, Nishanth G, Yi W, Brunn A, et al. The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13. Cell Mol Immunol. 2021; 18: 1512-27.

[10] Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. 2010; 329: 849-53.

[11] Nejak-Bowen K, Kikuchi A, Monga SP. Beta-catenin-NF-κB interactions in murine hepatocytes: a complex to die for. Hepatology. 2013; 57: 763-74.

[12] Hwang I, Choi YS, Jeon MY, Jeong S. NF-κB p65 represses β-catenin-activated transcription of cyclin D1. Biochem Biophys Res Commun. 2010; 403: 79-84.

[13] Bassiouni W, Ali M, a M, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J. 2021; 288: 7162-82.

[14] Cabral-Pacheco GA, Garza-Veloz I, Castruita-De La Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The roles of matrix Metalloproteinases and their inhibitors in human diseases. Int J Mol Sci. 2020; 21: 9739.

[15] De Bock M, Wang N, Decrock E, Bultynck G, Leybaert L. Intracellular cleavage of the Cx43 C-terminal domain by matrixmetalloproteases: a novel contributor to inflammation? Mediat Inflamm. 2015; 2015: 257471.

[16] Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, −7, −8, and −13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008; 112: 3455-64.

[17] Aota K, Ono S, Yamanoi T, Kani K, Momota Y, Azuma M. MMP-9 inhibition suppresses interferon-γ-induced CXCL10 production in human salivary gland ductal cells. Inflammation. 2019; 42: 2148-58.

[18] Klose A, Zigrino P, Mauch C. Monocyte/macrophage MMP-14 modulates cell infiltration and T-cell attraction in contact dermatitis but not in murine wound healing. Am J Pathol. 2013; 182: 755-64.

[19] Zhang Z, Amorosa LF, Coyle SM, Macor MA, Lubitz SE, Carson JL, et al. Proteolytic cleavage of AMPKα and intracellular MMP9 expression are both required for TLR4-mediated mTORC1 activation and HIF-1α expression in leukocytes. J Immunol. 2015; 195: 2452-60.

[20] Nissinen L, Kähäri VM. Matrix metalloproteinases in inflammation. Biochim Biophys Acta. 2014; 1840: 2571-80.

[21] Hu ZQ, Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, et al. Partial depletion of regulatory T cells enhances host inflammatory response against acute Pseudomonas aeruginosa infection after sepsis. Inflammation. 2018; 41: 1780-90.

[22] Yao RQ, Li ZX, Wang LX, Li YX, Zheng LY, Dong N, et al. Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis. Theranostics. 2022; 12: 4606-28.

[23] Vogel A, Martin K, Soukup K, Halfmann A, Kerndl M, Brunner JS, et al. JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory T cell induction. Cell Rep. 2022; 38: 110420.

[24] Zamora-Pineda J, Kumar A, Suh JH, Zhang M, Saba JD. Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J Exp Med. 2016; 213: 2773-91.

[25] Li JY, Ren C, Wang LX, Yao RQ, Dong N, Wu Y, et al. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. Cell Death Dis. 2021; 12: 834.

[26] Guak H, Al Habyan S, Ma EH, Aldossary H, Al-Masri M, Won SY, et al. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat Commun. 2018; 9: 2463.

[27] Chen W, Lian J, Ye JJ, Mo QF, Qin J, Hong GL, et al. Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression. Int Immunopharmacol. 2017; 52: 61-9.

[28] Zhao GJ, Li D, Zhao Q, Song JX, Chen XR, Hong GL, et al. Incidence, risk factors and impact on outcomes of secondary infection in patients with septic shock: an 8-year retrospective study. Sci Rep. 2016; 6: 38361.

[29] Wang Z, Li Z, Ji H. Direct targeting of β-catenin in the Wnt signaling pathway: current progress and perspectives. Med Res Rev. 2021; 41: 2109-29.

[30] Van Delft MA, Huitema LF, Tas SW. The contribution of NF-κB signalling to immune regulation and tolerance. Eur J Clin Investig. 2015; 45: 529-39.

[31] Karnam A, Bonam SR, Rambabu N, Wong SSW, Aimanianda V, Bayry J. Wnt-β-catenin Signaling in human dendritic cells mediates regulatory T-cell responses to fungi via the PD-L1 pathway. MBio. 2021; 12: e0282421.

[32] Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012; 31: 2714-36.

[33] Efron PA, Martins A, Minnich D, Tinsley K, Ungaro R, Bahjat FR, et al. Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis. J Immunol. 2004; 173: 3035-43.

[34] Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cell Mol Immunol. 2021; 18: 2461-71.

[35] Juurikka K, Butler GS, Salo T, Nyberg P, Åström P. The role of MMP8 in cancer: a systematic review. Int J Mol Sci. 2019; 20: 4506.

[36] Van Lint P, Libert C. Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 2006; 17: 217-23.

[37] Figiel I, Kruk PK, Zare˛ba-Kozioł M, Rybak P, Bijata M, Wlodarczyk J, et al. MMP-9 Signaling pathways that engage rho GTPases in brain plasticity. Cell. 2021; 10: 166.

[38] Guan C, Xiao Y, Li K, Wang T, Liang Y, Liao G. MMP-12 regulates proliferation of mouse macrophages via the ERK/P38 MAPK pathways during inflammation. Exp Cell Res. 2019; 378: 182-90.

[39] Marchant DJ, Bellac CL, Moraes TJ, Wadsworth SJ, Dufour A, Butler GS, et al. A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med. 2014; 20: 493-502.

[40] Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One. 2014; 9: e98819.

[41] Wong HR, Cvijanovich N, Allen GL, Lin R, Anas N, Meyer K, et al. Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 2009; 37: 1558-66.

[42] Solan PD, Dunsmore KE, Denenberg AG, Odoms K, Zingarelli B, Wong HR. A novel role for matrix metalloproteinase-8 in sepsis. Crit Care Med. 2012; 40: 379-87.

[43] Atkinson SJ, Varisco BM, Sandquist M, Daly MN, Klingbeil L, Kuethe JW, et al. Matrix Metalloproteinase-8 augments bacterial clearance in a juvenile sepsis model. Mol Med. 2016; 22: 455-63.

[44] Carreño LJ, Riedel CA, Kalergis AM. Induction of tolerogenic dendritic cells by NF-κB blockade and Fcγ receptor modulation. Methods Mol Biol. 2011; 677: 339-53.

[45] Smale ST. Dimer-specific regulatory mechanisms within the NF-κB family of transcription factors. Immunol Rev. 2012; 246: 193-204.

[46] Yu Y, Feng S, Wei S, Zhong Y, Yi G, Chen H, et al. Extracellular ATP activates P2X7R-NF-κB (p65) pathway to promote the maturation of bone marrow-derived dendritic cells of mice. Cytokine. 2019; 119: 175-81.

[47] Yu N, Wang S, Song X, Gao L, Li W, Yu H, et al. Low-dose radiation promotes dendritic cell migration and IL-12 production via the ATM/NF-KappaB pathway. Radiat Res. 2018; 189: 409-17.

[48] Fu C, Jiang A. Generation of tolerogenic dendritic cells via the E-cadherin/beta-catenin-signaling pathway. Immunol Res. 2010; 46: 72-8.

[49] Cho HH, Song JS, Yu JM, Yu SS, Choi SJ, Kim DH, et al. Differential effect of NF-kappaB activity on beta-catenin/Tcf pathway in various cancer cells. FEBS Lett. 2008; 582: 616-22.

[50] Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Chem. 2001; 276: 42276-86.

[51] Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013; 152: 25-38.

[52] Zirnheld AL, Villard M, Harrison AM, Kosiewicz MM, Alard P. β-Catenin stabilization in NOD dendritic cells increases IL-12 production and subsequent induction of IFN-γ-producing T cells. J Leukoc Biol. 2019; 106: 1349-58.

[53] Cohen SB, Smith NL, Mcdougal C, Pepper M, Shah S, Yap GS, et al. Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. J Immunol. 2015; 194: 210-22.