Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages

Michael R. Garbati, Laura E. Hays, R. Keaney Rathbun, Nathaniel Jillette, Kathy Chin, Muhsen Al-Dhalimy, Anupriya Agarwal, Amy E. Hanlon Newell, Susan Olson, Grover C. Bagby

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

Original languageEnglish (US)
Pages (from-to)455-465
Number of pages11
JournalJournal of Leukocyte Biology
Volume99
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Fanconi Anemia
Hypersensitivity
Macrophages
Cytokines
Chromosome Breakage
DNA Breaks
Mitomycin
DNA Damage
Fanconi Anemia Complementation Group Proteins
Hematopoietic Stem Cells

Keywords

  • DNA damage
  • TLR
  • TNF-α

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

Cite this

Garbati, M. R., Hays, L. E., Keaney Rathbun, R., Jillette, N., Chin, K., Al-Dhalimy, M., ... Bagby, G. C. (2016). Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. Journal of Leukocyte Biology, 99(3), 455-465. https://doi.org/10.1189/jlb.3A0515-201R

Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. / Garbati, Michael R.; Hays, Laura E.; Keaney Rathbun, R.; Jillette, Nathaniel; Chin, Kathy; Al-Dhalimy, Muhsen; Agarwal, Anupriya; Hanlon Newell, Amy E.; Olson, Susan; Bagby, Grover C.

In: Journal of Leukocyte Biology, Vol. 99, No. 3, 01.03.2016, p. 455-465.

Research output: Contribution to journalArticle

Garbati, MR, Hays, LE, Keaney Rathbun, R, Jillette, N, Chin, K, Al-Dhalimy, M, Agarwal, A, Hanlon Newell, AE, Olson, S & Bagby, GC 2016, 'Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages', Journal of Leukocyte Biology, vol. 99, no. 3, pp. 455-465. https://doi.org/10.1189/jlb.3A0515-201R
Garbati, Michael R. ; Hays, Laura E. ; Keaney Rathbun, R. ; Jillette, Nathaniel ; Chin, Kathy ; Al-Dhalimy, Muhsen ; Agarwal, Anupriya ; Hanlon Newell, Amy E. ; Olson, Susan ; Bagby, Grover C. / Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. In: Journal of Leukocyte Biology. 2016 ; Vol. 99, No. 3. pp. 455-465.
@article{4c5227caa04b4ba3bf9adc28d3739c6c,
title = "Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages",
abstract = "The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.",
keywords = "DNA damage, TLR, TNF-α",
author = "Garbati, {Michael R.} and Hays, {Laura E.} and {Keaney Rathbun}, R. and Nathaniel Jillette and Kathy Chin and Muhsen Al-Dhalimy and Anupriya Agarwal and {Hanlon Newell}, {Amy E.} and Susan Olson and Bagby, {Grover C.}",
year = "2016",
month = "3",
day = "1",
doi = "10.1189/jlb.3A0515-201R",
language = "English (US)",
volume = "99",
pages = "455--465",
journal = "Journal of Leukocyte Biology",
issn = "0741-5400",
publisher = "FASEB",
number = "3",

}

TY - JOUR

T1 - Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages

AU - Garbati, Michael R.

AU - Hays, Laura E.

AU - Keaney Rathbun, R.

AU - Jillette, Nathaniel

AU - Chin, Kathy

AU - Al-Dhalimy, Muhsen

AU - Agarwal, Anupriya

AU - Hanlon Newell, Amy E.

AU - Olson, Susan

AU - Bagby, Grover C.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

AB - The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

KW - DNA damage

KW - TLR

KW - TNF-α

UR - http://www.scopus.com/inward/record.url?scp=84961245395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961245395&partnerID=8YFLogxK

U2 - 10.1189/jlb.3A0515-201R

DO - 10.1189/jlb.3A0515-201R

M3 - Article

C2 - 26432900

AN - SCOPUS:84961245395

VL - 99

SP - 455

EP - 465

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

IS - 3

ER -