title: Toll-like receptor 2 and DC-SIGNR1 differentially regulate suppressors of cytokine signaling 1 in dendritic cells during Mycobacterium tuberculosis infection.
abstract: A hallmark of protective immunity during Mycobacterium tuberculosis (M. tb) infection is the regulated secretion of pro-inflammatory and regulatory cytokines. Suppressors of Cytokine Signaling (SOCS) are key regulators of cytokine secretion and function. In this study we investigated regulation of Toll-like receptor 2 (TLR2) and dendritic cell-specific ICAM-3 grabbing non-integrin receptor 1 (DC-SIGNR1)-mediated SOCS1 expression in DCs during M. tb infection. We show that, compared with TLR2, stimulating DC-SIGNR1 on DCs induces higher SOCS1 expression and lower interleukin-12 production. Co-stimulating DC-SIGNR1 and TLR2 differentially regulates SOCS1 expression depending on the relative concentration of their ligands. Stimulating DC-SIGNR1 with M. tb infection increases SOCS1 expression, while stimulating TLR2 with M. tb infection reduces SOCS1 expression. Knockdown of SOCS1 in DCs by siRNA enhances interleukin-12 transcription and protein expression upon DC-SIGNR1 stimulation. Raf-1 and Syk differentially regulate TLR2- and DC-SIGNR1-mediated SOCS1 expression. In addition, DC-SIGNR1 shows greater association with SOCS1 when compared with TLR2. Interestingly, compared with healthy asymptomatic individuals, peripheral blood mononuclear cells of patients with active tuberculosis disease showed higher expression of SOCS1, which was reduced following chemotherapy. Similarly, stimulating DC-SIGNR1 on DCs from M. tb-infected TLR2(-/-) mice enhanced SOCS1 expression that was reduced following chemotherapy. Further, knockdown of SOCS1 in mouse DCs or human peripheral blood mononuclear cells resulted in increased killing of virulent M. tb. These results indicate that TLR2 and DC-SIGNR1 differentially regulate SOCS1 expression during M. tb infection. This in turn regulates M. tb survival by governing key cytokine expression.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Varsha
authors.initials: V
authors.lastname: Srivastava
authors.forename: Mini
authors.initials: M
authors.lastname: Manchanda
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Rupak
authors.initials: R
authors.lastname: Singla
authors.forename: Digamber
authors.initials: D
authors.lastname: Behera
authors.forename: Gobardhan
authors.initials: G
authors.lastname: Das
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism*
chemical_list: C433029:CLEC4M protein, human; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2