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Age-Associated Defect in Human TLR-1/2 Function¹

David van Duin^*, Subhasis Mohanty^*, Venetta Thomas, Sandra Ginter, Ruth R. Montgomery, Erol Fikrig, Heather G. Allore, Ruslan Medzhitov and Albert C. Shaw^2,*

Sections of ^* Infectious Diseases and Rheumatology, Department of Internal Medicine and Program on Aging, and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21–30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF- (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF- (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Center of Excellence in Aging at Yale University, funded by the John A. Hartford Foundation, the Claude D. Pepper Older Americans Independence Center at Yale University (P30 AG021342) (to A.C.S. and D.V.D.), Yale School of Medicine Dean’s Pilot Project Grant in Translational Research (to A.C.S.), National Institute of Allergy and Infectious Diseases Grants NO1 AI 50031 (to E.F., R.R.M., and A.C.S.) and AI 053279 (to E.F.). D.V.D. is a Clinical Research Scholar in the Investigative Medicine Program, Yale University School of Medicine, supported by the Yale Mentored Clinical Research Scholars Program (National Institutes of Health Grant NCRR K12RR17594). R.M. is an Investigator of the Howard Hughes Medical Institute.

² Address correspondence and reprint requests to Dr. Albert C. Shaw, Section of Infectious Diseases, Yale University School of Medicine, 300 Cedar Street, Box 208022, New Haven, CT 06520. E-mail address: albert.shaw{at}yale.edu

³ Abbreviations used in this paper: Pam₃CSK₄, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride; LTA, lipoteichoic acid; NSAID, nonsteroidal anti-inflammatory drug; poly(U), polyuridylate; OspA, outer surface lipoprotein A.

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