Abstract
Background
Systemic Inflammatory Response Syndrome (SIRS) and sepsis remain leading causes of death. Despite many similarities, the two entities are very distinct clinically and immunologically. T-Lymphocytes play a key pivotal role in the pathogenesis and ultimately outcome following both SIRS and sepsis. Integrins are essential in the trafficking and migration of lymphocytes. They also serve vital roles in efficient wound healing and clearance of infections. Here, we investigate whether integrin expression, specifically β1 (CD29) and β2 (CD18), are disrupted in SIRS and sepsis, and assess differences in integrin expression between these two critically ill clinical categories.
Methods
T-Lymphocytes were isolated from whole blood collected from ICU patients exhibiting SIRS or sepsis. Samples were analyzed for CD18 (β2) and CD29 (β1) on CD3+ T cells through flow cytometry. Septic patients were stratified into either exclusively abdominal or non-abdominal sources of sepsis.
Results
CD18 was almost ubiquitously expressed on CD3+ T cells irrespective of clinical condition. However, CD29 (β1 integrin) was lowest in SIRS patients (20.4% of CD3+ T cells) when compared with either septic patients (35.5%) or healthy volunteers (54.1%). Furthermore, there was evidence of compartmentalization in septic patients, where abdominal sources had a greater percentage of CD3+CD29+ T cells (41.7%) when compared with those with non-abdominal sources (29.5%).
Conclusion
Distinct differences in T-cell integrin expression exists between patients in SIRS versus sepsis, as well as relative to the source of sepsis. Further work is needed to understand cause and effect relative to the progression from SIRS into sepsis.
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References
Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard G, Chiche J, Coopersmith C, Hotchkiss R, Levy M, Marshall J, Martin G, Opal S, Rubenfeld G, Van der Poll T, Vincent J, Angus D (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810
Rhodes A, Phillips G, Beale R, Cecconi M, Chiche J, De Backer D, Divatia J, Du B, Evans L, Ferrer R, Girardis M, Koulenti D, Machado F, Simpson S, Tan C, Wittebole X, Levy M (2015) The surviving sepsis campaign bundles and outcomes: results from the international multicentre prevalence study on sepsis (the IMPreSS) study. Intensive Care Med 41(9):1620–1628
Heffernan D, Monaghan S, Chung C, Cioffi W, Gravenstein S, Ayala A (2014) A divergent response of innate regulatory T-cells to sepsis in humans: circulating invariant natural killer T-cells are preserved. Hum Immunol 75(3):277–282
Thakkar R, Huang X, Lomas-Neira J, Heffernan D, Ayala A (2011) Sepsis and the immune response. In: Eremin O, Sewell H (eds) Essential immunology for surgeons. Oxford University Press, Oxford, pp 303–342
Binkowska A, Michalak G, Slotwinski R (2015) Current views on the mechanisms of immune responses to trauma and infection. Cent Eur J Immunol 40(2):206–216
Hotchkiss R, Monneret G, Payen D (2013) Sepsis induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13(12):862–874
Venet F, Chung C, Monneret G, Huang X, Horner B, Garber M, Ayala A (2008) Regulatory T cell populations in sepsis and trauma. J Leukoc Biol 83(3):523–535
Shubin N, Monaghan S, Heffernan D, Chung C, Ayala A (2013) B and T lymphocyte attenuator expression on CD4 + T-cells associates with sepsis and subsequent infections. Crit Care 17(6):R276
Young J, Monaghan S, Chung C, Cioffi W, Ayala A, Heffernan D (2015) Divergent invariant natural killer T-cell response to sepsis of abdominal versus non-adominal origin in human beings. Surg Infect 16(1):29–35
Drewry A, Samra N, Skrupky L, Fuller B, Compton S, Hotchkiss R (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42(5):383–391
Heffernan D, Monaghan S, Thakkar R, Machan J, Cioffi W, Ayala A (2012) Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit Care 16(1):R12
Benechet A, Menon M, Khanna K (2014) Visualizing T cell migration in situ. Front Immunol 5(363):1–12
Heffernan D, Monaghan S, Thakkar R, Tran M, Chung C, Gregory S, Cioffi W, Ayala A (2013) Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function. Shock 40(2):122–128
Mitroulis I, Alexaki V, Kourtzelis I, Ziogas A, Hajishengallis G, Chavakis T (2015) Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 147:123–135
Zhang Y, Wang H (2013) Integrin signaling and function in immune cells. Immunology 135(4):268–275
Nourshargh S, Alon R (2014) Leukocyte migration into inflamed tissues. Immunity 41(5):694–707
Koivisto L, Heino J, Hakkinen L, Larjava H (2014) Integrins in wound healing. Adv Wound Care 3(12):762–783
Baaten B, Cooper A, Swain S, Bradley L (2013) Location, location, location: the impact of migratory heterogeneity on T cell function. Front Immunol 4:311
Valignat M, Theodoly O, Gucciardi A, Hogg N, Lellouch A (2013) T lymphocytes orient against the direction of fluid flow during LFA-1 mediated migration. Biophys J 104(2):322–331
Reichardt P, Patzak I, Jones K, Etemire E, Gunzer M, Hogg N (2013) A role for LFA-1 in delaying T-lymphocyte egress from lymph nodes. EMBO J 32(6):829–843
Tan S (2012) The Leukocyte beta2 (CD18) integrins: the structure, functional regulation and signalling. Biosci Rep 32(3):241–269
Cantor J, Rose D, Slepak M, Ginsberg M (2015) Fine tuning tumor immunity with integrin trans-regulation. Cancer Immunol Res 3(6):661–667
Uotila L, Jahan F, Soto Hinojosa L, Melandri E, Gronholm M, Gahmberg C (2014) Specific phosphorylations transmit signals from leukocyte beta2 to beta1 integrins and regulate adhesion. J Biol Chem 289(46):32230–32242
Verma N, Kelleher D (2014) Adaptor regulation of LFA-1 signaling in T lymphocyte migration: Potential druggable targets for immunotherapies? Eur J Immunol 44(12):3484–3499
Dupre L, Houmadi R, Tang C, Rey-Barroso J (2015) T Lymphocyte migration: an action movie starring the actin and associated actors. Front Immunol 6:586
Gerner R, Moschen A, Tilg H (2013) Targeting T and B lymphocytes in inflammatory bowel diseases: lessons from clinical trials. Dig Dis 31(3–4):328–335
Weaver L, Bao F, Dekaban G, Hryciw T, Schultz S, Cain D, Brown A (2015) CD11b integrin blockade reduces the systemic inflammatory respose syndrome after traumatic brain injury in rats. Exp Neurol 271:409–422
Gorlino C, Ranocchia R, Harman M, Garcia M, Crespo M, Moron G, Maletto B, Pistoresi-Palencia M (2014) Neutrophils exhibit differential requirements for homing molecules in their lymphatic and blood trafficking into draining lymph nodes. J Immunol 193(4):1966–1974
Wostradowski T, Gudi V, Pul R, Gingele S, Lindquist J, Stangel M, Lindquist S (2015) Effect of interferon-beta1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients. Clin Exp Immunol 182(2):162–172
Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2(2):123–128
Ding Z, Jia S, Marshall J, Downey G, Waddell T (2006) Up-regulation of functional CXCR4 expression on human lymphocytes in sepsis. Crit Care Med 34(12):3011–3017
Manetti M, Guiducci S, Romano E, Rosa I, Ceccarelli C, Mello T, Milia A, Conforti M, Ibba-Manneschi L, Matucci-Cerinic M (2013) Differential expression of junctional adhesion molecules in different stages of systemic sclerosis. Arthritis Rheum 65(1):247–257
Sladojevic N, Stamatovic S, Keep R, Grailer J, Sarma J, Ward P, Andjelkovic A (2014) Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury. Neurobiol Dis 67:57–70
Huang Y, Clarke F, Karimi M, Roy N, Williamson E, Okumura M, Mochizuki K, Chen E, Park T, Debes G, Zhang Y, Curran T, Kambayasgi T, Burkhardt J (2015) CRK proteins selectively regulate T cell migration into inflammed tissues. J Clin Investig 125(3):1019–1032
Morrison V, MacPherson M, Savinko T, Lek H, Prescott A, Fagerholm S (2013) The beta2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. Blood 122(8):1428–1436
Gonzalez-Alvaro I, Munoz C, Garcia-Vicuna R, Sabando P, Cabanas C, Sanchez-Madrid F, Diaz-Gonzalez F (1998) Interference of nonsteroidal antiinflammatory drugs with very late activation antgen 4/vascular cells adhesion molecule 1-mediated lymphocyte-endothelial cell adhesion. Arthritis Rheum 41(9):1677–1688
Rosenthal-Allieri M, Ticchioni M, Breittmayer J, Breittmayer J, Shimizu Y, Bernard A (2005) Influence of beta 1 integrin intracytoplasmic domains in the regulation of VLA-4 mediated adhesion of human T cells to VCAM-1 under flow conditions. J Immunol 17(2):1214–1223
Parkash J, Cimino I, Ferraris N, Casoni F, Wray S, Cappy H, Prevot V, Giacobini P (2012) Suppression of b1- integrin in gonadotropin-releasing hormone cells disrupts migration and axonal extension resulting in severe reproductive alterations. J Neurosci 32(47):16992–17002
Howe G, Addison C (2012) Beta-1 integrin: an emerging player in the modulation of tumorigenesis and response to therapy. Cell Adhes Migr 6(2):71–77
Kadioglu A, De Filippo K, Bangert M, Fernandes V, Richards L, Jones K, Andrew P, Hogg N (2011) The integrins Mac-1 and alpha4beta 1 perform cruical roles in neutrophil and T cell recruitment to lungs during Streptoccus pneumoniae infection. J Immunol 186(10):5907–5915
Luque A, Gomez M, Puzon W, Takada Y, Sanchez-Madrid F, Cabanas C (1996) Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355–425) of the common beta-1 chain. J Biol Chem 271(19):11067–11075
Langer H, Chavakis T (2009) Leukocyte-endothelial interactions in inflammation. J Cell Mol Med 13(7):1211–1220
Nachtsheim R, Dudley B, McNeil P (2006) The peritoneal cavity is a distinct compartment of angiogenic molecular mediators. J Surg Res 134(1):28–35
Cavaillon J, Annane D (2006) Compartmentalization of the inflammatory response in sepsis and SIRS. J Endotoxin Res 12(3):151–170
Stromberg P, Woolsey C, Clark A, Clark J, Turnbull I, McConnell K, Chang K, Chung C, Ayala A, Buchman T, Hotchkiss R, Coopersmith C (2009) CD4 + lymphocytes control gut epithelial apoptosis and mediate survival in sepsis. FASEB J 23(6):1817–1825
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No author has any conflict of interest with respect to this manuscript. No author has received any research grant from any company for this project. None of the authors has received any speaker honorarium, or owns any stock in any company that has any relationship to this study.
No animal was used in this study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Full Rhode Island Hospital Institutional Review Board approval was obtained and active during the period of the study. Informed assent was obtained from all individual participants included in the study.
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Heffernan, D.S., Monaghan, S.F. & Ayala, A. Lymphocyte integrin expression differences between SIRS and sepsis patients. Ir J Med Sci 186, 981–987 (2017). https://doi.org/10.1007/s11845-016-1525-4
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DOI: https://doi.org/10.1007/s11845-016-1525-4