CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

Mohd Hafeez Faridi, Samia Q. Khan, Wenpu Zhao, Ha Won Lee, Mehmet M. Altintas, Kun Zhang, Vinay Kumar, Andrew R. Armstrong, Carmelo Carmona-Rivera, Jessica M. Dorschner, Abigail M. Schnaith, Xiaobo Li, Yogita Ghodke-Puranik, Erica Moore, Monica Purmalek, Jorge Irizarry-Caro, Tingting Zhang, Rachael Day, Darren Stoub, Victoria Hoffmann & 24 others Shehryar Jehangir Khaliqdina, Prachal Bhargava, Ana M. Santander, Marta Torroella-Kouri, Biju Issac, David J. Cimbaluk, Andrew Zloza, Rajeev Prabhakar, Shashank Deep, Meenakshi Jolly, Kwi Hye Koh, Jonathan S. Reichner, Elizabeth M. Bradshaw, Jianfeng Chen, Luis F. Moita, Peter S. Yuen, Wanxia Li Tsai, Bhupinder Singh, Jochen Reiser, Swapan K. Nath, Timothy B. Niewold, Roberto I Vazquez-Padron, Mariana J. Kaplan, Vineet Gupta

Research output: Contribution to journalArticle

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Abstract

Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/ FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-?, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.

Original languageEnglish (US)
Pages (from-to)1271-1283
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number4
DOIs
StatePublished - Apr 3 2017

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Autoimmunity
Systemic Lupus Erythematosus
Inbred MRL lpr Mouse
Interferon Regulatory Factor-3
Inflammation
Interferon Type I
Integrins
Single Nucleotide Polymorphism
Leukocytes
Macrophages
Wounds and Injuries
Therapeutics
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Faridi, M. H., Khan, S. Q., Zhao, W., Lee, H. W., Altintas, M. M., Zhang, K., ... Gupta, V. (2017). CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. Journal of Clinical Investigation, 127(4), 1271-1283. https://doi.org/10.1172/JCI88442

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. / Faridi, Mohd Hafeez; Khan, Samia Q.; Zhao, Wenpu; Lee, Ha Won; Altintas, Mehmet M.; Zhang, Kun; Kumar, Vinay; Armstrong, Andrew R.; Carmona-Rivera, Carmelo; Dorschner, Jessica M.; Schnaith, Abigail M.; Li, Xiaobo; Ghodke-Puranik, Yogita; Moore, Erica; Purmalek, Monica; Irizarry-Caro, Jorge; Zhang, Tingting; Day, Rachael; Stoub, Darren; Hoffmann, Victoria; Khaliqdina, Shehryar Jehangir; Bhargava, Prachal; Santander, Ana M.; Torroella-Kouri, Marta; Issac, Biju; Cimbaluk, David J.; Zloza, Andrew; Prabhakar, Rajeev; Deep, Shashank; Jolly, Meenakshi; Koh, Kwi Hye; Reichner, Jonathan S.; Bradshaw, Elizabeth M.; Chen, Jianfeng; Moita, Luis F.; Yuen, Peter S.; Tsai, Wanxia Li; Singh, Bhupinder; Reiser, Jochen; Nath, Swapan K.; Niewold, Timothy B.; Vazquez-Padron, Roberto I; Kaplan, Mariana J.; Gupta, Vineet.

In: Journal of Clinical Investigation, Vol. 127, No. 4, 03.04.2017, p. 1271-1283.

Research output: Contribution to journalArticle

Faridi, MH, Khan, SQ, Zhao, W, Lee, HW, Altintas, MM, Zhang, K, Kumar, V, Armstrong, AR, Carmona-Rivera, C, Dorschner, JM, Schnaith, AM, Li, X, Ghodke-Puranik, Y, Moore, E, Purmalek, M, Irizarry-Caro, J, Zhang, T, Day, R, Stoub, D, Hoffmann, V, Khaliqdina, SJ, Bhargava, P, Santander, AM, Torroella-Kouri, M, Issac, B, Cimbaluk, DJ, Zloza, A, Prabhakar, R, Deep, S, Jolly, M, Koh, KH, Reichner, JS, Bradshaw, EM, Chen, J, Moita, LF, Yuen, PS, Tsai, WL, Singh, B, Reiser, J, Nath, SK, Niewold, TB, Vazquez-Padron, RI, Kaplan, MJ & Gupta, V 2017, 'CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1271-1283. https://doi.org/10.1172/JCI88442
Faridi, Mohd Hafeez ; Khan, Samia Q. ; Zhao, Wenpu ; Lee, Ha Won ; Altintas, Mehmet M. ; Zhang, Kun ; Kumar, Vinay ; Armstrong, Andrew R. ; Carmona-Rivera, Carmelo ; Dorschner, Jessica M. ; Schnaith, Abigail M. ; Li, Xiaobo ; Ghodke-Puranik, Yogita ; Moore, Erica ; Purmalek, Monica ; Irizarry-Caro, Jorge ; Zhang, Tingting ; Day, Rachael ; Stoub, Darren ; Hoffmann, Victoria ; Khaliqdina, Shehryar Jehangir ; Bhargava, Prachal ; Santander, Ana M. ; Torroella-Kouri, Marta ; Issac, Biju ; Cimbaluk, David J. ; Zloza, Andrew ; Prabhakar, Rajeev ; Deep, Shashank ; Jolly, Meenakshi ; Koh, Kwi Hye ; Reichner, Jonathan S. ; Bradshaw, Elizabeth M. ; Chen, Jianfeng ; Moita, Luis F. ; Yuen, Peter S. ; Tsai, Wanxia Li ; Singh, Bhupinder ; Reiser, Jochen ; Nath, Swapan K. ; Niewold, Timothy B. ; Vazquez-Padron, Roberto I ; Kaplan, Mariana J. ; Gupta, Vineet. / CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 4. pp. 1271-1283.
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abstract = "Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/ FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-?, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.",
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AU - Zhao, Wenpu

AU - Lee, Ha Won

AU - Altintas, Mehmet M.

AU - Zhang, Kun

AU - Kumar, Vinay

AU - Armstrong, Andrew R.

AU - Carmona-Rivera, Carmelo

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AU - Schnaith, Abigail M.

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AU - Day, Rachael

AU - Stoub, Darren

AU - Hoffmann, Victoria

AU - Khaliqdina, Shehryar Jehangir

AU - Bhargava, Prachal

AU - Santander, Ana M.

AU - Torroella-Kouri, Marta

AU - Issac, Biju

AU - Cimbaluk, David J.

AU - Zloza, Andrew

AU - Prabhakar, Rajeev

AU - Deep, Shashank

AU - Jolly, Meenakshi

AU - Koh, Kwi Hye

AU - Reichner, Jonathan S.

AU - Bradshaw, Elizabeth M.

AU - Chen, Jianfeng

AU - Moita, Luis F.

AU - Yuen, Peter S.

AU - Tsai, Wanxia Li

AU - Singh, Bhupinder

AU - Reiser, Jochen

AU - Nath, Swapan K.

AU - Niewold, Timothy B.

AU - Vazquez-Padron, Roberto I

AU - Kaplan, Mariana J.

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